Selective modulation of renal nerves

ABSTRACT

Methods for treating a patient using therapeutic renal neuromodulation and associated devices, systems, and methods are disclosed herein. One aspect of the present technology is directed to methods including selectively neuromodulating afferent or efferent renal nerves. One or more measurable physiological parameters corresponding to systemic sympathetic overactivity or hyperactivity in the patient can thereby be reduced. Selectively neuromodulating afferent renal nerves can include inhibiting sympathetic neural activity in nerves proximate a renal pelvis. This can include, for example, neuromodulating via fluid within the renal pelvis. Selectively neuromodulating efferent renal nerves can include inhibiting sympathetic neural activity in nerves proximate a portion of a renal artery or a renal branch artery proximate a renal parenchyma. This can include, for example, neuromodulating via a therapeutic element within the portion of the renal artery or the renal branch artery.

CROSS-REFERENCE TO RELATED APPLICATION(S)

The present application is a continuation of U.S. patent applicationSer. No. 14/379,834, filed Aug. 20, 2014, now allowed, which is a U.S.National Phase Application under 35 U.S.C. 371 of InternationalApplication No. PCT/US2013/029526, filed Mar. 7, 2013, which claimspriority to U.S. Provisional Patent Application No. 61/608,022, filedMar. 7, 2012, all of which are incorporated herein in their entiretiesby reference.

TECHNICAL FIELD

The present technology relates generally to the modulation of renalnerves. In particular, several embodiments are directed to the selectivemodulation of renal nerves, e.g., the selective modulation of afferentrenal nerves over efferent renal nerves and the selective modulation ofefferent renal nerves over afferent renal nerves.

BACKGROUND

The sympathetic nervous system (SNS) is a primarily involuntary bodilycontrol system typically associated with stress responses. Fibers of theSNS extend through tissue in almost every organ system of the human bodyand can affect characteristics such as pupil diameter, gut motility, andurinary output. Such regulation can have adaptive utility in maintaininghomeostasis or in preparing the body for rapid response to environmentalfactors. Chronic activation of the SNS, however, is a common maladaptiveresponse that can drive the progression of many disease states.Excessive activation of the renal SNS in particular has been identifiedexperimentally and in humans as a likely contributor to the complexpathophysiology of hypertension, states of volume overload (such asheart failure), and progressive renal disease. For example, radiotracerdilution has demonstrated increased renal norepinephrine spillover ratesin patients with essential hypertension.

Sympathetic nerves of the kidneys terminate in the blood vessels, thejuxtaglomerular apparatus, and the renal tubules, among otherstructures. Stimulation of the renal sympathetic nerves can cause, forexample, increased renin release, increased sodium reabsorption, andreduced renal blood flow. These and other neural-regulated components ofrenal function are considerably stimulated in disease statescharacterized by heightened sympathetic tone. For example, reduced renalblood flow and glomerular filtration rate as a result of renalsympathetic efferent stimulation is likely a cornerstone of the loss ofrenal function in cardio-renal syndrome, i.e., renal dysfunction as aprogressive complication of chronic heart failure. Pharmacologicstrategies to thwart the consequences of renal sympathetic stimulationinclude centrally-acting sympatholytic drugs, beta blockers (intended toreduce renin release), angiotensin-converting enzyme inhibitors andreceptor blockers (intended to block the action of angiotensin II andaldosterone activation consequent to renin release), and diuretics(intended to counter the renal sympathetic mediated sodium and waterretention). These pharmacologic strategies, however, have significantlimitations including limited efficacy, compliance issues, side effects,and others.

BRIEF DESCRIPTION OF THE DRAWINGS

Many aspects of the present disclosure can be better understood withreference to the following drawings. The components in the drawings arenot necessarily to scale. Instead, emphasis is placed on illustratingclearly the principles of the present disclosure.

FIG. 1 is a partially-schematic view illustrating a renalneuromodulation system configured in accordance with an embodiment ofthe present technology.

FIG. 2 is a cross-sectional view illustrating a kidney and a mediumwithin the renal pelvic anatomy of the kidney in accordance with anembodiment of the present technology.

FIG. 3 is a cross-sectional view of the kidney and medium of FIG. 2 anda treatment device including a therapeutic element within the renalpelvic anatomy in accordance with an embodiment of the presenttechnology.

FIG. 4 is a cross-sectional view of the kidney, medium, and treatmentdevice of FIG. 3 illustrating moving the therapeutic element totreatment locations within the renal pelvic anatomy in accordance withan embodiment of the present technology.

FIG. 5 is a cross-sectional view illustrating a kidney and a treatmentdevice including a therapeutic element within the renal artery of thekidney in accordance with an embodiment of the present technology.

FIG. 6 is a cross-sectional view of the kidney and treatment device ofFIG. 5 illustrating moving the therapeutic element to treatmentlocations within the renal branch arteries of the kidney in accordancewith an embodiment of the present technology.

FIG. 7 is a block diagram illustrating a method of selectivelymodulating afferent renal nerves in accordance with an embodiment of thepresent technology.

FIG. 8 is a block diagram illustrating a method of selectivelymodulating efferent renal nerves in accordance with an embodiment of thepresent technology.

FIG. 9 is a conceptual diagram illustrating the sympathetic nervoussystem and how the brain communicates with the body via the sympatheticnervous system.

FIG. 10 is an enlarged anatomical view illustrating nerves innervating aleft kidney to form a renal plexus surrounding a left renal artery.

FIGS. 11A and 11B are anatomical and conceptual views, respectively,illustrating a human body including a brain and kidneys and neuralefferent and afferent communication between the brain and kidneys.

FIGS. 12A and 12B are anatomic views illustrating, respectively, anarterial vasculature and a venous vasculature of a human.

DETAILED DESCRIPTION

The present technology is generally directed to the selective modulationof renal nerves. Specific details of several embodiments of the presenttechnology are described herein with reference to FIGS. 1-12B. Althoughmany of the embodiments are described herein with respect to devices,systems, and methods for modulation of renal nerves usingelectrically-induced, thermally-induced, and chemically-inducedapproaches, other applications and other treatment modalities inaddition to those described herein are within the scope of the presenttechnology. Additionally, other embodiments of the present technologycan have different configurations, components, or procedures than thosedescribed herein. For example, other embodiments can include additionalelements and features beyond those described herein or be withoutseveral of the elements and features shown and described herein.

For ease of reference, throughout this disclosure identical referencenumbers are used to identify similar or analogous components orfeatures, but the use of the same reference number does not imply thatthe parts should be construed to be identical. Indeed, in many examplesdescribed herein, the identically-numbered parts are distinct instructure and/or function.

Generally, unless the context indicates otherwise, the terms “distal”and “proximal” within this disclosure reference a position relative toan operator or an operator's control device. For example, “proximal” canrefer to a position closer to an operator or an operator's controldevice, and “distal” can refer to a position that is more distant froman operator or an operator's control device. The headings providedherein are for convenience only.

I. RENAL NEUROMODULATION

Renal neuromodulation is the partial or complete incapacitation or othereffective disruption of nerves innervating the kidneys, e.g., nervesterminating in or originating from a kidney or in structures closelyassociated with a kidney. In particular, renal neuromodulation caninclude inhibiting, reducing, and/or blocking neural communication alongneural fibers (e.g., efferent and/or afferent neural fibers) innervatingthe kidneys. Such incapacitation can be long-term (e.g., permanent orfor periods of months, years, or decades) or short-term (e.g., forperiods of minutes, hours, days, or weeks). While long-term disruptionof the renal nerves can be desirable for alleviating symptoms and othersequelae associated with central sympathetic overstimulation over longerperiods of time, short-term modulation of the renal nerves may also bedesirable. For example, some patients may benefit from short-termmodulation to address issues relating to an acute stage of fluidretention or heart failure.

As described in greater detail below with reference to FIGS. 9-12B,sympathetic nerves (e.g., efferent and/or afferent neural fibers) cancontribute to a number of cardiovascular-related diseases and conditions(e.g., hypertension, heart failure, left ventricular hypertrophy,cardio-renal syndrome, etc.), metabolic-related diseases and conditions(metabolic syndrome, insulin resistance, diabetes, etc.),endocrine-related diseases and conditions (e.g., polycystic ovarysyndrome, osteoporosis, erectile dysfunction, etc.) among others. Forexample, obesity and hypertension can be characterized by increasedefferent sympathetic drive to the kidneys and increased systemicsympathetic nerve firing modulated by afferent signaling from renalsensory nerves. The role of renal sympathetic nerves as contributors tothe pathogenesis of elevated blood pressure, particularly in obesepatients, has been demonstrated both experimentally and in humans. Apartfrom its role in cardiovascular regulation, sympathetic nervous systemactivation also has metabolic effects resulting in increased lipolysisand increased levels of fatty acids in plasma, increased hepaticgluconeogenesis, and alterations in pancreatic insulin release. Chronicsympathetic activation predisposes to the development of insulinresistance, which is often associated with obesity and hypertensionwhich can also be a key feature of many endocrine-related conditionspolycystic ovary syndrome, erectile dysfunction, etc.).

Renal neuromodulation can contribute to the systemic reduction ofsympathetic tone or drive. Accordingly, renal neuromodulation isexpected to be useful in treating clinical conditions associated withsystemic sympathetic overactivity or hyperactivity, particularlyconditions associated with central sympathetic overstimulation. Forexample, renal neuromodulation is expected to efficaciously treathypertension, heart failure, acute myocardial infarction, metabolicsyndrome, insulin resistance, diabetes, left ventricular hypertrophy,chronic and end stage renal disease, inappropriate fluid retention inheart failure, cardio-renal syndrome, polycystic kidney disease,polycystic ovary syndrome, osteoporosis, erectile dysfunction, andsudden death, among other conditions. Furthermore, renal neuromodulationcan potentially benefit a variety of organs and bodily structuresinnervated by sympathetic nerves.

Several properties of the renal vasculature may inform the design oftreatment devices and associated methods for achieving selective renalneuromodulation, for example, via intravascular access, and imposespecific design requirements for such devices. Specific designrequirements may include accessing the renal artery, a ureter, a renalpelvis, a major renal calyx, a minor renal calyx, and/or anothersuitable structure; facilitating stable contact between the energydelivery elements of such devices and a luminal surface or wall of thesuitable targeted structure, and/or effectively and selectivelymodulating the renal nerves with the neuromodulatory apparatus.

II. SELECTED EXAMPLES OF NEUROMODULATION MODALITIES

Various techniques can be used to partially or completely incapacitateneural pathways, such as those innervating the kidney. Renalneuromodulation, in accordance with embodiments of the presenttechnology, can be electrically-induced, thermally-induced,chemically-induced, or induced in another suitable manner or combinationof manners at one or more suitable treatment locations during atreatment procedure. For example, the purposeful application ofradiofrequency (RF) energy (monopolar and/or bipolar), pulsed RF energy,microwave energy, optical energy, ultrasound energy (e.g., delivered bycatheter, extracorporeal, high-intensity focused ultrasound (HIFU)),cryotherapeutic energy, direct heat energy, radiation (e.g., infrared,visible, gamma), chemicals (e.g., drugs or other agents), orcombinations thereof to tissue at a treatment location can induce one ormore desired effects at the treatment location, e.g., broadly across thetreatment location or at localized regions of the treatment location.The treatment location can be proximate (e.g., at or near) a vessel orchamber wall (e.g., a wall of a renal artery, a ureter, a renal pelvis,a major renal calyx, a minor renal calyx, and/or another suitablestructure), and the treated tissue can include tissue proximate thetreatment location. For example, with regard to a renal artery, atreatment procedure can include modulating nerves in the renal plexus,which lay intimately within or adjacent to the adventitia of the renalartery.

In some embodiments, the purposeful application of energy (e.g.,electrical energy, thermal energy, etc.) to tissue can induce one ormore desired thermal heating and/or cooling effects on localized regionof the renal artery or other target tissue (e.g., a ureter, a renalpelvis, a major renal calyx, a minor renal calyx, and/or anothersuitable structure). Some embodiments of the present technology, forexample, include cooling tissue at a target site in a manner thatmodulates neural function. Accordingly, renal neuromodulation caninclude a cryotherapeutic treatment modality alone or in combinationwith another treatment modality. For example, sufficiently cooling atleast a portion of a sympathetic renal nerve can slow or potentiallyblock conduction of neural signals to produce a prolonged or permanentreduction in renal sympathetic activity. This effect can occur as aresult of cryotherapeutic tissue damage, which can include, for example,direct cell injury (e.g., necrosis), vascular or luminal injury (e.g.,starving cells from nutrients by damaging supplying blood vessels),and/or sublethal hypothermia with subsequent apoptosis. Exposure tocryotherapeutic cooling can cause acute cell death (e.g., immediatelyafter exposure) and/or delayed cell death, e.g., during tissue thawingand subsequent hyperperfusion. Neuromodulation using a cryotherapeutictreatment in accordance with embodiments of the present technology caninclude cooling a structure proximate (e.g., adjacent) an inner surfaceof a vessel or chamber wall such that tissue is effectively cooled to adepth where sympathetic renal nerves reside. For example, a coolingassembly of a cryotherapeutic device can be cooled to the extent that itcauses therapeutically-effective, cryogenic renal neuromodulation. Insome embodiments, a cryotherapeutic treatment modality can includecooling that is not configured to cause neuromodulation. For example,the cooling can be at or above cryogenic temperatures and can be used tocontrol neuromodulation via another treatment modality, e.g., to reducedamage to non-targeted tissue when targeted tissue adjacent to thenon-targeted tissue is heated.

Cryotherapeutic treatment can be beneficial in certain embodiments. Forexample, rapidly cooling tissue can provide an analgesic effect suchthat cryotherapeutic treatment can be less painful than other treatmentmodalities. Neuromodulation using cryotherapeutic treatment cantherefore require less analgesic medication to maintain patient comfortduring a treatment procedure compared to neuromodulation using othertreatment modalities. Additionally, reducing pain can reduce patientmovement and thereby increase operator success and/or reduce proceduralcomplications. Cryogenic cooling also typically does not causesignificant collagen tightening, and therefore is not typicallyassociated with vessel stenosis. In some embodiments, cryotherapeutictreatment can include cooling at temperatures that can cause therapeuticelements to adhere to moist tissue. This can be beneficial because itcan promote stable, consistent, and continued contact during treatment.The typical conditions of treatment can make this an attractive featurebecause, for example, patients can move during treatment, cathetersassociated with therapeutic elements can move, and/or respiration cancause the kidneys to rise and fall and thereby move the renal arteriesand other structures associated with the kidneys. In addition, bloodflow is pulsatile and can cause structures associated with the kidneysto pulse. Cryogenic adhesion also can facilitate intravascular orintraluminal positioning, particularly in relatively-small structures(e.g., relatively-short arteries) in which stable intravascular orintraluminal positioning can be difficult to achieve.

As an alternative to or in conjunction with cryotherapeutic cooling,other suitable energy delivery techniques, such as electrode-based ortransducer-based approaches, can be used for therapeutically-effectiveand selective renal neuromodulation. Electrode-based or transducer-basedtreatment can include delivering electricity and/or another form ofenergy to tissue at a treatment location to stimulate and/or heat thetissue in a manner that modulates neural function. For example,sufficiently stimulating and/or heating at least a portion of asympathetic renal nerve can slow or potentially block conduction ofneural signals to produce a prolonged or permanent reduction in renalsympathetic activity. As noted previously, suitable energy modalitiescan include, for example, RF energy (monopolar and/or bipolar), pulsedRF energy, microwave energy, ultrasound energy (e.g., intravascularlydelivered ultrasound, extracorporeal ultrasound, HIFU), laser energy,optical energy, magnetic energy, direct heat, radiation (e.g., infrared,visible, gamma), or other suitable energy modalities alone or incombination. Where a system uses a monopolar configuration, a returnelectrode or ground patch fixed externally on the subject can be used.Moreover, electrodes (or transducers or other energy delivery elements)can be used alone or with other electrodes or transducers in amulti-electrode or multi-transducer array. Examples of suitablemulti-electrode devices are described in U.S. patent application Ser.No. 13/281,360, filed Oct. 25, 2011, and incorporated herein byreference in its entirety. Other suitable devices and technologies, suchas cryotherapeutic devices, are described in U.S. patent applicationSer. No. 13/279,330, filed Oct. 23, 2011, and additional thermal devicesare described in U.S. patent application Ser. No. 13/279,205, filed Oct.21, 2011, each of which are incorporated herein by reference in theirentireties. Furthermore, the energy can be applied from within the body(e.g., within the vasculature or other body lumens in a catheter-basedapproach) and/or from outside the body, e.g., via an applicatorpositioned outside the body. In some embodiments, energy can be used toreduce damage to non-targeted tissue when targeted tissue adjacent tothe non-targeted tissue is subjected to neuromodulating cooling.

Ultrasound energy (e.g., HIFU energy) can be beneficial in certainembodiments. Focused ultrasound is an example of a transducer-basedtreatment modality that can be delivered from outside the body. In someembodiments, focused ultrasound treatment can be performed in closeassociation with imaging, e.g., magnetic resonance, computed tomography,fluoroscopy, ultrasound (e.g., intravascular or intraluminal), opticalcoherence tomography, or another suitable imaging modality. For example,imaging can be used to identify an anatomical position of a treatmentlocation, e.g., as a set of coordinates relative to a reference point.The coordinates can then entered into a focused ultrasound deviceconfigured to change the power, angle, phase, or other suitableparameters to generate an ultrasound focal zone at the locationcorresponding to the coordinates. In some embodiments, the focal zonecan be small enough to localize therapeutically-effective heating at thetreatment location while partially or fully avoiding potentially harmfuldisruption of nearby structures. To generate the focal zone, theultrasound device can be configured to pass ultrasound energy through alens, and/or the ultrasound energy can be generated by a curvedtransducer or by multiple transducers in a phased array (curved orstraight).

Thermal effects of neuromodulation treatment can include both ablationand non-ablative thermal alteration or damage, (e.g., via sustainedheating and/or resistive heating) to partially or completely disrupt theability of a nerve to transmit a signal. Desired thermal heatingeffects, for example, can include raising the temperature of targetneural fibers to a desired target temperature above a first threshold toachieve non-ablative alteration, or above a second, higher threshold toachieve ablative thermal alteration. In some embodiments, the targettemperature can be higher than about body temperature (e.g., about 37°C.) but less than about 45° C. for non-ablative thermal alteration, andthe target temperature can be higher than about 45° C. for ablativethermal alteration. More specifically, exposure to thermal energy inexcess of a body temperature of about 37° C., but below a temperature ofabout 45° C., may induce thermal non-ablative alteration, for example,via moderate heating of target neural fibers or of vascular or luminalstructures that perfuse the target neural fibers. In cases wherevascular structures are affected, the target neural fibers may be deniedperfusion resulting in necrosis of the neural tissue. For example, thismay induce non-ablative thermal alteration in the fibers or structures.Exposure to heat above a temperature of about 45° C., or above (e.g.,higher than about 60° C.), may induce thermal alteration via substantialheating of the fibers or structures. For example, such highertemperatures may thermally ablate the target neural fibers or ofvascular or luminal structures that perfuse the target fibers. In somepatients, it can be desirable to heat tissue to temperatures that aresufficient to thermally ablate the target neural fibers or the vascularor luminal structures, but that are less than about 90° C., or are lessthan about 85° C., or less than about 80° C., and/or less than about 75°C. Other embodiments can include heating tissue to a variety of othersuitable temperatures.

In some embodiments, renal neuromodulation can include a chemical-basedtreatment modality alone or in combination with another treatmentmodality. Neuromodulation using chemical-based treatment can includedelivering one or more chemicals (e.g., drugs or other agents) to tissueat a treatment location in a manner that modulates neural function. Thechemical, for example, can be selected to affect the treatment locationgenerally or to selectively affect some structures at the treatmentlocation over other structures. In some embodiments, the chemical can beguanethidine, ethanol, phenol, vincristine, a neurotoxin, or anothersuitable agent selected to alter, damage, or disrupt nerves. In someembodiments, energy (e.g., light, ultrasound, or another suitable typeof energy) can be used to activate the chemical and/or to cause thechemical to become more bioavailable. A variety of suitable techniquescan be used to deliver chemicals to tissue at a treatment location. Forexample, chemicals can be delivered via one or more devices, such asneedles originating outside the body or within the vasculature or otherbody lumens or delivery pumps (see, e.g., U.S. Pat. No. 6,978,174, thedisclosure of which is hereby incorporated by reference in itsentirety). In an intravascular example, a catheter can be used tointravascularly position a therapeutic element including a plurality ofneedles (e.g., micro-needles) that can be retracted or otherwise blockedprior to deployment. In other embodiments, a chemical can be introducedinto tissue at a treatment location via simple diffusion through avessel wall, electrophoresis, or another suitable mechanism. Similartechniques can be used to introduce chemicals that are not configured tocause neuromodulation, but rather to facilitate neuromodulation viaanother treatment modality. Examples of such chemicals include, but arenot limited to, anesthetic agents and contrast agents.

III. SELECTIVE RENAL NEUROMODULATION

The kidneys are innervated with both afferent and efferent nerves. As asensory organ, the kidney comprises both chemoreceptors andbaroreceptors that are connected with the central nervous system viaafferent nerve fibers, which can then regulate blood pressure andcentral sympathetic outflow. The efferent renal nerves carry signalsfrom the central nervous system to the kidneys. Afferent and efferentrenal nerves can affect the progression of disease states (e.g.,hypertension) associated with systemic sympathetic overactivity orhyperactivity in different ways. For example, activation of renalefferent nerves can increase sodium reabsorption/retention, increaserenin release (and subsequent renin-angiotensin-aldosterone system(RAAS) activation), and decrease renal blood flow, all of which can haveeffects on central sympathetic drive such as increasing blood pressure.As discussed above, renal sensory afferent nerves can stimulate thehypothalamus to increase systemic sympathetic discharge (e.g., activatethe centrally-mediated sympathetic nervous system). This direct systemicactivation can have such consequences as increasing peripheral vascularresistance and increasing sympathetic drive to the heart (whichincreases heart rate and cardiac contractility), thereby increasingblood pressure.

Adverse consequences of chronic sympathetic overactivity, such ashypertension, left ventricular hypertrophy (LVH), ventriculararrhythmias, sudden cardiac death, insulin resistance, diabetes,metabolic syndrome among other endocrine disorders (e.g., polycysticovary syndrome, erectile dysfunction, etc.) are documented bothexperimentally and in humans. While both efferent and afferent renalnerve fibers can contribute to central sympathetic drive including, forexample, overactivity or hyperactivity of the central sympatheticsystem, there is evidence from studies of animal dorsal rhizotomy aswell as human studies using direct recordings of muscle sympatheticnerve activity (MSNA) that sensory afferent signals originating fromdiseased or damaged kidneys are contributors to initiating andsustaining elevated central sympathetic outflow within this subjectgroup. While the specific factors that bind and activate the renalnerves (e.g., at the site of these diseased or damaged kidneys) are notwell understood, and without being bound by theory, it is thought thatafferent renal nerve activation can be initiated by mechanoreceptor- andchemoreceptor-mediated secretion of adenosine in response to, forexample, ischemic-induced hypoxia.

Positive outcomes have been reported from neuromodulation of both theafferent and efferent renal nerves. As evidenced by positive, long-termoutcomes in kidney transplant patients, both afferent and efferentcommunication with the kidneys can be disabled in some cases withoutserious complications. Much of the functionality of efferent renalnerves, for example, can be redundant to other bodily systems.Accordingly, some approaches to renal neuromodulation can benon-selective with respect to afferent and efferent renal nerves. Forexample, modulation of a renal plexus via a renal artery (e.g.,intravascular access) typically affects both afferent and efferent renalnerves. There can be reasons, however, to modulate afferent or efferentrenal nerves selectively.

Selective renal neuromodulation can include modulating afferent renalnerves preferentially over efferent renal nerves or, in anotherembodiment, modulating efferent renal nerves preferentially overafferent renal nerves. Complete selectivity may not be necessary, butrather several embodiments include modulating one of the efferent orafferent renal nerves to a greater extent than the other. Kidneystypically include a greater number of efferent nerves than afferentnerves, so selective modulation of afferent renal nerves can stillinvolve modulating a greater number of efferent renal nerves thanafferent renal nerves in several embodiments. For example, a treatmentprocedure for selective modulation of afferent renal nerves can modulatea greater percentage of the total afferent renal nerves of a kidney anda lower percentage of the total efferent renal nerves of the kidney.Similarly, selective modulation of efferent renal nerves can modulate agreater percentage of the total efferent renal nerves of a kidney and alower percentage of the total afferent renal nerves of the kidney. Insome embodiments of treatment procedures in accordance with the presenttechnology, selective modulation of afferent renal nerves can includemodulating greater than about 50% (e.g., greater than about 60% orgreater than about 70%) of the total afferent renal nerves of a kidneyand less than about 50% (e.g., less than about 40% or less than about30%) of the total efferent renal nerves of the kidney. Similarly, anembodiment of a treatment procedure for selective modulation of efferentrenal nerves can include modulating greater than about 50% (e.g.,greater than about 60% or greater than about 70%) of the total efferentrenal nerves of a kidney and less than about 50% (e.g., less than about40% or less than about 30%) of the total afferent renal nerves of thekidney.

In some cases, certain disease states can be associated with higheractivity of afferent renal nerves compared to the activity of efferentrenal nerves, while other disease states are associated with higheractivity of efferent renal nerves than with the activity of afferentrenal nerves. For example, selective modulation of one of afferent andefferent renal nerves can have a greater effect on some or all diseasestates associated with systemic sympathetic overactivity orhyperactivity than selective modulation of the other. In some cases,selective modulation of afferent renal nerves can have a greater effecton renal conditions (e.g., polycystic kidney disease) than selectivemodulation of efferent renal nerves. Furthermore, with respect tocertain disease states, selective renal neuromodulation can provide someof, most of, all of, or more than the beneficial effect of non-selectiverenal neuromodulation. For example, selective modulation of afferentrenal nerves may be therapeutically effective for the treatment oferectile dysfunction about equally or to a greater extent thannon-selective renal neuromodulation.

Neuromodulation selective to one of the afferent or efferent renalnerves may, for example, cause less disruption of normal renal-nerveactivity than non-selective renal neuromodulation. Preserving morefunctionality of one of the afferent or efferent renal nerves comparedto non-selective renal neuromodulation can, in some instances, havespecific utility. For example, preserving some or all renal afferentfunctionality may be useful to reduce the possibility of late detectionof kidney stones that would otherwise have been detectable earlier dueto a pain response carried by afferent renal nerves. This can beparticularly useful in patients diagnosed as having cystinuria or ashaving an increased risk of developing kidney stones relative to thegeneral population, e.g., based on a familial history of kidney stones.Preserving renal efferent functionality may be useful, for example, insome patients having an inability or a reduced ability to compensate formissing renal efferent functionality with other bodily systems.

Selective renal neuromodulation in accordance with embodiments of thepresent technology can include preferentially targeting one of theafferent or efferent renal nerves over the other based on theirpredominant anatomical positions. With respect to a single kidney, therenal plexus includes both afferent and efferent renal nerves toward therenal ostium where the renal artery meets the aorta. The majority ofafferent renal nerves of the renal plexus, however, branch offrenal-nerve bundles of the renal plexus before entering the renalparenchyma. These afferent renal nerves are mostly located and/orterminate along the renal pelvic wall. In contrast, most of the efferentrenal nerves of the renal plexus continue into the renal parenchyma.With this anatomy in mind, a relatively-high concentration of afferentrenal nerves can be found at the renal pelvis and a relatively-highconcentration of efferent renal nerves can be found at the renal plexusnear the renal parenchyma. Other locations having relatively-highconcentrations of afferent or efferent renal nerves are also possible.

IV. SELECTED EXAMPLES OF RENAL NEUROMODULATION SYSTEMS

FIG. 1 is a partially-schematic diagram illustrating a renalneuromodulation system 100 that can include a first treatment device102, a second treatment device 104, and an energy source or console 106.The system 100 can further include a first cable 108 extending betweenthe console 106 and the first treatment device 102 and a second cable110 extending between the console 106 and the second treatment device104. The first and second treatment devices 102, 104 can be configuredfor different treatment modalities or different aspects of the sametreatment modality. For example, the first treatment device 102 can beconfigured to perform or facilitate renal neuromodulation from withinthe vasculature or other body lumens and the second treatment device 104can be configured to perform or facilitate renal neuromodulation fromoutside the body. In other embodiments, the system 100 can include onlythe first treatment device 102 or only the second treatment device 104.Furthermore, in some embodiments, rather than being a handheld device,the second treatment device 104 can be a stationary device mounted neara chair or bed on which a patient can be positioned. For example, thesecond treatment device 104 can be automatically positioned relative tothe chair or bed based on entered coordinates.

As shown in FIG. 1, the first treatment device 102 can include a firsthandle 112, a therapeutic element 114, and an elongated shaft 116extending between the first handle 112 and the therapeutic element 114.The second treatment device 104 can include a second handle 118 and ahead 120. With regard to the first treatment device 102, the shaft 116can be configured to locate the therapeutic element 114 intravascularlyor in other body lumens (e.g., via a renal artery or a ureter) at atreatment location in or near a vessel or other body lumen associatedwith renal function, and the therapeutic element 114 can be configuredto provide or support therapeutically-effective, renal neuromodulationat the treatment location. In some embodiments, the shaft 116 and thetherapeutic element 114 can be 3, 4, 5, 6, or 7 French or anothersuitable size. Furthermore, the shaft 116 and the therapeutic element114 can be partially or fully radiopaque and/or can include radiopaquemarkers corresponding to measurements, e.g., every 5 cm.

Intravascular delivery can include percutaneously inserting a guide wire(not shown) within the vasculature and moving the shaft 116 and thetherapeutic element 114 along the guide wire until the therapeuticelement 114 reaches the treatment location. For example, the shaft 116and the therapeutic element 114 can include a guide-wire lumen (notshown) configured to receive the guide wire in an over-the-wire orrapid-exchange configuration. Other body lumens, such as ducts (e.g., aureter) or internal chambers, can be treated by non-percutaneouslypassing the shaft 116 and therapeutic element 114 through externallyaccessible passages of the body. In some embodiments, a distal end ofthe therapeutic element 114 can terminate in an atraumatic rounded tipor cap (not shown). The first treatment device 102 can also be asteerable or non-steerable catheter device (e.g., a guide catheter)configured for use without a guide wire. Use of a guide wire, forexample, is not included in some ureteric catheterization techniques.

The therapeutic element 114 can have a single state or configuration, orit can be convertible between a plurality of states or configurations.For example, the therapeutic element 114 can be configured to bedelivered to a treatment location in a delivery state and to provide orsupport therapeutically-effective, renal neuromodulation in a deployedstate. In these and other embodiments, the therapeutic element 114 canhave different sizes and/or shapes in the delivery and deployed states.For example, the therapeutic element 114 can have a low-profileconfiguration in the delivery state and an expanded configuration in thedeployed state. The therapeutic element 114 can be converted (e.g.,placed or transformed) between the delivery and deployed states viaremote actuation, e.g., using an actuator 122 of the first handle 112.The actuator 122 can include a knob, a pin, a lever, a button, a dial,or another suitable control component. In other embodiments, thetherapeutic element 114 can be transformed between the delivery anddeployed states using other suitable mechanisms or techniques.

The therapeutic element 114 can include an elongated member (not shown)that can be configured to curve (e.g., arch) in the deployed state,e.g., in response to movement of the actuator 122. For example, theelongated member can be at least partially helical/spiral in thedeployed state. In other embodiments, the therapeutic element 114 caninclude a balloon (not shown) that can be configured to be at leastpartially inflated in the deployed state. An elongated member, forexample, can be well suited for carrying one or more heating elements,electrodes or transducers and for delivering direct heat,electrode-based or transducer-based treatment. A balloon, for example,can be well suited for containing refrigerant (e.g., during or shortlyafter liquid-to-gas phase change) and for delivering cryotherapeutictreatment. A balloon can also be used in some embodiments for carryingsuitable RF conducting electrodes. In some embodiments, the therapeuticelement 114 can be configured for intravascular, transvascular,intraluminal, and/or transluminal delivery of chemicals. For example,the therapeutic element 114 can include one or more openings (notshown), and chemicals (e.g., drugs or other agents) can be deliverablethrough the openings. For transvascular or transluminal delivery, thetherapeutic element 114 can include one or more needles (not shown)(e.g., retractable needles) and the openings can be at end portions ofthe needles.

The console 106 can be configured to control, monitor, supply, orotherwise support operation of the first and second treatment devices102, 104. In some embodiments, the console 106 can be separate from andin communication with the first and/or second treatment devices 102,104. In other embodiments, the console 106 can be contained within or bea component of the first and/or second treatment devices 102, 104. Instill further embodiments, the console 106 can be configured for usewith only one of the first and second treatment devices 102, 104 and thesystem 100 can include another console configured for use with the otherof the first and second treatment devices 102, 104. In still otherembodiments, the first treatment device 102 and/or the second treatmentdevice 104 can be self-contained and/or otherwise configured foroperation without connection to the console 106. As shown in FIG. 1, theconsole 106 can include a primary housing 124 having a display 126. Thesystem 100 can include a first control device 128 along the first cable108 and a second control device 130 along the second cable 110configured, respectively, to initiate, terminate, and/or adjustoperation of the first treatment device 102 and/or the second treatmentdevice 104 directly and/or via the console 106. In other embodiments,the system 100 can include another suitable control mechanism. Forexample, the first control device 128 can be incorporated into the firsthandle 112 and/or the second control device 130 can be incorporated intothe second handle 118.

The console 106 can be configured to execute an automated controlalgorithm 132 and/or to receive control instructions from an operator.Furthermore, the console 106 can be configured to provide feedback to anoperator before, during, and/or after a treatment procedure via thedisplay 126 and/or an evaluation/feedback algorithm 134. In someembodiments, the console 106 can include a processing device (not shown)having processing circuitry, e.g., a microprocessor. The processingdevice can be configured to execute stored instructions relating to thecontrol algorithm 132 and/or the evaluation/feedback algorithm 134.Furthermore, the console 106 can be configured to communicate with thefirst and/or second treatment devices 102, 104, e.g., via the firstand/or second cables 108, 110, respectively. For example, thetherapeutic element 114 of the first treatment device 102 can include asensor (not shown) (e.g., a temperature sensor, a pressure sensor, or aflow rate sensor) and a sensor lead (not shown) (e.g., an electricallead or a pressure lead) configured to carry a signal from the sensor tothe first handle 112. The first cable 108 can be configured to carry thesignal from the first handle 112 to the console 106.

The console 106 can have different configurations depending on thetreatment modalities of the first and second treatment devices 102, 104.For example, when one or both of the first and second treatment devices102, 104 is configured for electrode-based or transducer-basedtreatment, the console 106 can include an energy generator (not shown)configured to generate RF energy, pulsed RF energy, microwave energy,optical energy, ultrasound energy (e.g., intravascularly deliveredultrasound, extracorporeal ultrasound, HIFU), magnetic energy, directheat energy, or another suitable type of energy. In some embodiments,the console 106 can include an RF generator operably coupled to one ormore electrodes (not shown) of the therapeutic element 114 of the firsttreatment device 102 and a focused-ultrasound generator operably coupledto one or more electrodes or transducers (not shown) of the head 120 ofthe second treatment device 104.

When the first treatment device 102 is configured for cryotherapeutictreatment, the console 106 can include a refrigerant reservoir (notshown) and can be configured to supply the first treatment device 102with refrigerant, e.g., pressurized refrigerant in liquid orsubstantially liquid phase. Similarly, when the first treatment device102 is configured for chemical-based treatment, the console 106 caninclude a chemical reservoir (not shown) and can be configured to supplythe first treatment device 102 with the chemical. In some embodiments,the first treatment device 102 can include an adapter (not shown) (e.g.,a luer lock) configured to be operably coupled to a syringe (not shown).The adapter can be fluidly connected to a lumen (not shown) of thetreatment device 102, and the syringe can be used, for example, tomanually deliver one or more chemicals to the treatment location, towithdraw material from the treatment location, to inflate a balloon (notshown) of the therapeutic element 114, to deflate a balloon of thetherapeutic element 114, or for another suitable purpose.

In certain embodiments, a neuromodulation device for use in the methodsdisclosed herein may combine two or more energy modalities. For example,the device may include both a hyperthermic source of ablative energy anda hypothermic source, making it capable of, for example, performing bothRF neuromodulation and cryo-neuromodulation. The distal end of thetreatment device may be straight (for example, a focal catheter),expandable (for example, an expanding mesh or cryoballoon), or have anyother configuration (e.g., a helical coil). Additionally oralternatively, the treatment device may be configured to carry out oneor more non-ablative neuromodulatory techniques. For example, the devicemay comprise a means for diffusing a drug or pharmaceutical compound atthe target treatment area (e.g., a distal spray nozzle).

V. SELECTED EXAMPLES OF TREATMENT PROCEDURES FOR SELECTIVE MODULATION OFAFFERENT RENAL NERVES

Treatment procedures for selective modulation of afferent renal nervesin accordance with embodiments of the present technology can includeapplying a treatment modality at one or more treatment locationsproximate a structure having a relatively-high concentration of afferentrenal nerves and/or closer to afferent renal nerves than efferent renalnerves. In some embodiments, at least one treatment location can beproximate the renal pelvic anatomy of a kidney, which can include, forexample, the renal pelvis, the ureteropelvic junction, the majorcalyces, the minor calyces, and/or other suitable structures. Ingeneral, the renal pelvic anatomy can have a larger and more irregularwall structure than the renal artery. Furthermore, nerve tissue can beshallower around the renal pelvic anatomy than around the renal artery.For example, a majority of afferent renal nerves at the renal pelvicanatomy can be within about 2 mm (e.g., about 1 mm) of the insidesurface of the epithelium. In contrast, a majority of nerves in therenal plexus can be a greater distance from an inner surface of therenal artery. A therapeutic element of a treatment device can bepositioned at a treatment location within the renal pelvic anatomy, forexample, via a catheterization path including the urethra, the bladder,and the ureter, but other suitable catheterization paths may be used.Catheterization can be guided, for example, using imaging, e.g.,magnetic resonance, computed tomography, fluoroscopy, ultrasound (e.g.,intravascular or intraluninal), optical coherence tomography, or anothersuitable imaging modality.

In some embodiments, a medium, such as a fluid, a particulate, asolution, and/or a colloid, within the renal pelvic anatomy can beactivated to cause neuromodulation of nearby renal nerves. For example,a naturally-occurring medium (e.g., urine) or an artificially-introducedmedium (e.g., saline) within the renal pelvic anatomy can be heated,cooled, energized, or otherwise activated in a manner sufficient tocause neuromodulation of renal nerves (e.g., afferent renal nerves or acombination of afferent and efferent renal nerves) around the renalpelvic anatomy. FIG. 2 is a cross-sectional view illustrating a kidney200 including a renal pelvis 202 and a medium 204 within the renalpelvis 202. As shown in FIG. 2, the kidney 200 can further include arenal artery 206, a renal vein 208, and a ureter 210 extending from therenal pelvis 202. The renal artery 206 can branch into a plurality ofrenal branch arteries 212 of the kidney 200. The renal pelvis 202 canbranch into a plurality of calyces 214 (one labeled) of the kidney 200.The medium 204 can enhance the distribution of a neuromodulating effectacross the relatively large and irregular surface of the renal pelvicanatomy. The medium 204 can be introduced, for example, through theureter 210, e.g., via a needle (not shown) or a catheter (not shown). Insome embodiments, the ureter 210 can be at least partially blocked(e.g., clamped) to at least partially maintain the renal pelvic anatomyin a full state. The relatively-shallow positioning of the afferentrenal nerves around the renal pelvis 202 can facilitate selectiveneuromodulation of the afferent rental nerves relative to the efferentrenal nerves. For example, the medium 204 can be activated in a mannerthat causes therapeutically-effective renal neuromodulation in a zonewithin about 3 mm (e.g., within about 2 mm or within about 1.5 mm) of aninner surface of the renal pelvic wall. In some cases, the epithelium ofthe renal pelvic anatomy can recover from such a treatment, and all ormost of the modulated nerves can remain non-functional.

One or more of the treatment modalities discussed above can be used toactivate the medium 204 from an external device outside of the body. Forexample, the medium 204 can be heated using ultrasound (e.g., HIFU)directed into the renal pelvis 202 from an external ultrasoundtransducer device (not shown) located outside the body. When theultrasound is applied, the location/orientation of the renal pelvis 202relative to the external ultrasound transducer device and/or therelatively large size of the renal pelvis 202 may reduce the need forexact placement of a focal zone. In some embodiments, for example, themedium 204 can absorb and distribute heat relatively evenly over therenal pelvic wall even if the focal zone is not centrally positioned inthe renal pelvis 202. Furthermore, because the renal pelvis 202 isrelatively large, the likelihood of locating the focal zone at anundesirable location may be relatively low. In some embodiments, themedium 204 can be artificially introduced and selected to enhanceneuromodulation. For example, the medium 204 can include a microbubblecontrast agent or another material configured to increase the heatingeffect of ultrasound. Suitable microbubble contrast agents can haveshells (e.g., made from albumin, lipid, or galactose) and gas cores(e.g., including air). In other embodiments, focused ultrasound can beused to neuromodulate portions of the renal pelvic anatomy without themedium 204.

In other embodiments, the medium 204 can be activated using an electrodeor another therapeutic element located within the renal pelvis 202. FIG.3 is a cross-sectional view illustrating a treatment device including ashaft 300 extending through the ureter 210 and a therapeutic element 302at a distal portion of the shaft 300 within the renal pelvis 202. Insome embodiments, the shaft 300 and the therapeutic element 302 can beportions of a treatment device at least partially corresponding to thefirst treatment device 102 shown in FIG. 1. With reference to FIG. 3,the therapeutic element 302 can be configured to activate the medium204. For example, the therapeutic element 302 can include an electrode(not shown) (e.g., a radiofrequency electrode or a microwave electrode),a cryotherapeutic cooling assembly (not shown), a direct heating element(not shown), or another suitable activating component. In someembodiments, the therapeutic element 302 can include an opening (notshown) and can be configured to chemically activate the medium 204 byintroducing a chemical into the medium. 204 via the opening. In theseand other embodiments, the therapeutic element 302 can further includean electrode (not shown) configured to deliver at least a portion of thechemical into the renal pelvic wall by electrophoresis.

In some embodiments, therapeutic neuromodulation can be via thetherapeutic element 302 and not via the medium 204. FIG. 4, for example,is a cross-sectional view illustrating moving the therapeutic element302 between a first treatment location 400 and a second treatmentlocation 402 during a treatment procedure. The shaft 300, for example,can be steerable (e.g., via one or more pull wires, a steerable guide orsheath catheter, etc.) and can be configured to sequentially move thetherapeutic element 302 into the first and second treatment locations400, 402. At the first treatment location 400, the therapeutic element302 can contact or be in close proximity to a portion of the renalpelvic wall near the renal artery 206. At the second treatment location402, the therapeutic element 302 can contact or be in close proximity toa wall of one of the calyces 214. A variety of other suitable treatmentlocations are also possible throughout the renal pelvic anatomy.Furthermore, a treatment procedure can include treatment at any suitablenumber of treatment locations, e.g., a single treatment location, twotreatment locations (as shown in FIG. 4), or more than two treatmentlocations. The treatment locations can correspond to portions of therenal pelvic anatomy proximate relatively-high concentrations ofafferent renal nerves. At each treatment location, the therapeuticelement 302 can be activated to cause modulation of nerves proximate thetreatment location. Activating the therapeutic element 302 can include,for example, heating, cooling, electrifying, or applying anothersuitable treatment modality at the treatment location.

Activating the therapeutic element 302 can further include applyingvarious energy modalities at varying power levels, intensities and forvarious durations for achieving modulation of nerves proximate thetreatment location. In some embodiments, power levels, intensitiesand/or treatment duration can be determined and employed using variousalgorithms for ensuring modulation of nerves at select distances (e.g.,depths) away from the treatment location. Furthermore, as notedpreviously, in some embodiments, the therapeutic element 302 can beconfigured to introduce (e.g., inject) a chemical (e.g., a drug) intotissue at the treatment location. Such chemicals or agents can beapplied at various concentrations depending on treatment location andthe relative depth of the target nerves.

The therapeutic element 302 can be configured to accommodate the anatomyof the renal pelvis 202 and/or another suitable structure. For example,the therapeutic element 302 can include a balloon (not shown) configuredto inflate to a shape generally corresponding to the shape of the renalpelvis 202. The balloon can be configured to deliver cryotherapeuticcooling or another suitable treatment modality over all or a portion therenal pelvis 202. In these and other embodiments, the therapeuticelement 302 can be configured to apply a suitable treatment modality ata relatively shallow depth to avoid disrupting structures beyond thetargeted renal nerves. For example, the therapeutic element 302 caninclude a plurality of electrodes (not shown) having a bipolarconfiguration, which can facilitate shallower treatment than otherconfigurations. In another example, the therapeutic element 302 caninclude a plurality of heating elements (not shown) for directlyapplying heat at the treatment location. In some embodiments, thisarrangement is expected to form shallower lesions in the wall of therenal pelvis 202 or a wall of one of the calyces 214 as compared withcertain other energy modalities. Moreover, in some embodiments, therapyusing direct heat application may require less power to operate thanseveral other energy modalities. During a treatment procedure in whichthe therapeutic element 302 is configured to cause neuromodulationdirectly, the medium 204 can shape the renal pelvis 202 (e.g., in anopen and/or slightly-distended state) to facilitate accurate placementof the therapeutic element 302. In other embodiments, the therapeuticelement 302 can be used to neuromodulate portions of the renal pelvis202 without the medium 204.

The medium 204 can have other functions in addition to or instead ofbeing a vehicle for neuromodulation and shaping the renal pelvis 202.For example, since afferent renal nerves can carry a visceral painsignal, it can be useful to accompany neuromodulation of afferent renalnerves with local anesthesia. In some embodiments, a local anestheticagent (e.g., procaine) can be introduced into the renal pelvis 202,e.g., via an opening (not shown) in the therapeutic element 302. Sincenerve endings around the renal pelvis 202 are relatively shallow, theanesthetic agent can be highly localized and still effective.Furthermore, in some embodiments the medium 204 can be configured tofacilitate imaging (e.g., magnetic resonance, computed tomography,fluoroscopy, ultrasound (e.g., intravascular or intraluminal), opticalcoherence tomography, or another suitable imaging modality) during atreatment procedure. For example, the medium 204 can include a contrastmaterial, e.g., a contrast material configured to preferentially absorblight at wavelengths between about 500 nm and about 1100 nm. Suitablecontrast materials include, for example, indocyanine green, methyleneblue, toluidine blue, aminolevulinic acid, chlorin compounds,phthalocyanines, porphyrins, purpurins, and texaphyrins, among others.Imaging the renal pelvic anatomy can be used to identify portions of therenal pelvic anatomy suitable for treatment and/or to guide execution ofa treatment within the renal pelvic anatomy. Guiding execution caninclude, for example, guiding placement of the therapeutic element 302(e.g., by guiding steering operations of the shaft 300) and/or guidingplacement of a focal zone of a focused ultrasound device.

In some embodiments, the medium 204 can help to protect the innerepithelium of the renal pelvic anatomy. For example, the medium 204 caninclude an epithelial-protective agent (e.g., polyethylene glycol)configured to preserve tissue integrity or otherwise reduce damage toepithelial cells while nerves proximate the epithelial cells aremodulated. Similarly, the medium 204 can be cooled to counteract heatused to modulate the nerves proximate the epithelial cells. For example,the therapeutic element 302 can be configured to cool the medium 204.When the medium 204 protects the epithelial cells (e.g., via anepithelial-protective agent and/or cooling), the proximate nerves can bemodulated, for example, with focused ultrasound. The focal zone of thefocused ultrasound can include a maximum-intensity portion closer to thenerves being modulated than to the epithelial cells being protected.Placement of the focal zone and the protective effect of the medium 204can function cooperatively to cause a relatively-steep temperaturegradient between the epithelial cells and the nerves.

Other treatment procedures for selective modulation of afferent renalnerves in accordance with embodiments of the present technology are alsopossible. Treatment procedures for selective modulation of afferentrenal nerves in accordance with embodiments of the present technologyare expected to improve one or more measurable physiological parametersin patients corresponding to systemic sympathetic overactivity orhyperactivity. For example, the treatment procedures are expected toreduce MSNA (e.g., at least about 10%) and/or whole body norepinephrinespillover (e.g., at least about 20%) in patients. These and otherclinical effects are expected to be detectable immediately after atreatment procedure or after a delay, e.g., of 1, 2, or 3 months.

VI. SELECTED EXAMPLES OF TREATMENT PROCEDURES FOR SELECTIVE MODULATIONOF EFFERENT RENAL NERVES

Treatment procedures for selective modulation of efferent renal nervesin accordance with embodiments of the present technology can includeapplying a treatment modality at one or more treatment locationsproximate a structure having a relatively-high concentration of efferentrenal nerves and/or closer to efferent renal nerves than afferent renalnerves. In some embodiments, the treatment locations can be proximateportions of the renal artery 206 and/or the renal branch arteries 212near the renal parenchyma. Portions of the renal plexus (not shown)proximate the treatment locations can have lower concentrations ofafferent renal nerves than other portions of renal plexus. For example,the portions of the renal plexus proximate the treatment locations canhave less than about 50% (e.g., less than about 25%) of a concentrationof afferent renal nerves at a portion of the renal plexus proximate anostium (not shown) of the renal artery 206. A therapeutic element of atreatment device can be positioned at a treatment location within therenal artery, for example, via a catheterization path including thefemoral artery and the aorta or another suitable catheterization path,e.g., a radial or brachial catheterization path. Catheterization can beguided, for example, using imaging, e.g., magnetic resonance, computedtomography, fluoroscopy, ultrasound (e.g., intravascular orintraluminal), optical coherence tomography, or another suitable imagingmodality.

FIG. 5 is a cross-sectional view showing neuromodulation at a treatmentlocation within the renal artery 206. FIG. 6 is a cross-sectional viewshowing neuromodulation at treatment locations within the renal brancharteries 212. Referring to FIGS. 5 and 6 together, a treatment deviceincluding a shaft 500 and a therapeutic element 502 can be extendedtoward the renal artery 206 to locate the therapeutic element 502 at atreatment location within the renal artery 206 and/or the renal brancharteries 212. The therapeutic element 502 can be configured forneuromodulation at the treatment location via a suitable treatmentmodality, e.g., cryotherapeutic, direct heat, electrode-based,transducer-based, or chemical-based. In some embodiments, the shaft 500and the therapeutic element 502 can be portions of a treatment device atleast partially corresponding to the first treatment device 102 shown inFIG. 1. The shaft 500 can be steerable (e.g., via one or more pullwires, a steerable guide or sheath catheter, etc.) and can be configuredto move the therapeutic element 502 between treatment locations. At eachtreatment location, the therapeutic element 502 can be activated tocause modulation of nerves proximate the treatment location. Activatingthe therapeutic element 502 can include, for example, heating, cooling,stimulating, or applying another suitable treatment modality at thetreatment location. Activating the therapeutic element 502 can furtherinclude applying various energy modalities at varying power levels,intensities and for various durations for achieving modulation of nervesproximate the treatment location. In some embodiments, power levels,intensities and treatment duration can be determined and employed usingvarious algorithms for ensuring modulation of nerves at select distances(e.g., depths) away from the treatment location. Additionally, in someembodiments, the therapeutic element 502 can be configured to introduce(e.g., inject) a chemical a drug or other agent) into target tissue atthe treatment location. Such chemicals or agents can be applied atvarious concentrations depending on treatment location and the relativedepth of the target nerves.

In some embodiments, the therapeutic element 502 can be configured toradially expand into a deployed state 504 at the treatment location. Inthe deployed state 504, the therapeutic element 502 can be configured tocontact an inner wall of the renal artery 206 and to form afully-circumferential lesion without the need for repositioning. Forexample, the therapeutic element 502 can be configured to form a lesionor series of lesions (e.g., a helical/spiral lesion or a discontinuouslesion) that is fully-circumferential overall, but generallynon-circumferential at longitudinal segments of the treatment location.This can facilitate precise and efficient treatment with a lowpossibility of vessel stenosis. In other embodiments, the therapeuticelement 502 can be configured to form a partially-circumferential lesionor a fully-circumferential lesion at a single longitudinal segment ofthe treatment location. During treatment, the therapeutic element 502can be configured to partially or fully occlude the renal artery 206.Partial occlusion can be useful, for example, to reduce renal ischemia,and full occlusion can be useful, for example, to reduce interference(e.g., warming or cooling) caused by blood flow through the treatmentlocation. In some embodiments, the therapeutic element 502 can beconfigured to cause therapeutically-effective neuromodulation (e.g.,using ultrasound energy) without contacting a vessel wall.

The therapeutic element 502 can be configured to accommodate the anatomyof the renal artery 206 and/or the renal branch arteries 212, and/oranother suitable structure. For example, the therapeutic element 502 caninclude a balloon (not shown) configured to inflate to a size generallycorresponding to the internal size of the renal artery 206 and/or therenal branch arteries 212, and/or another suitable structure. In someembodiments, the therapeutic element 502 can be an implantable deviceand a treatment procedure can include locating the therapeutic element502 at the treatment location using the shaft 500 fixing the therapeuticelement 502 at the treatment location, separating the therapeuticelement 502 from the shaft 500, and withdrawing the shaft 500. Othertreatment procedures for selective modulation of efferent renal nervesin accordance with embodiments of the present technology are alsopossible.

Treatment procedures for selective modulation of efferent renal nervesin accordance with embodiments of the present technology are expected toimprove one or more measurable physiological parameters in patientscorresponding to systemic sympathetic overactivity or hyperactivity. Forexample, the treatment procedures are expected to reduce MSNA (e.g., atleast about 10%) and/or whole body norepinephrine spillover (e.g., atleast about 20%) in patients. These and other clinical effects areexpected to be detectable immediately after a treatment procedure orafter a delay, e.g., of 1, 2, or 3 months.

VII. METHODS FOR SELECTIVE RENAL NEUROMODULATION

Disclosed herein are several embodiments of methods directed toselective neuromodulation of afferent and/or efferent renal nerves. Themethods disclosed herein may represent various advantages over a numberof conventional approaches and techniques in that they allow for thepotential targeting of elevated sympathetic drive, which may be a keymediator of multiple manifestations of cardiovascular, metabolic andendocrine-related conditions. Also, the disclosed methods provide forlocalized treatment and limited duration treatment regimens (e.g.,one-time treatment), thereby reducing patient long-term treatmentcompliance issues.

In certain embodiments, the methods provided herein comprise performingselective renal neuromodulation, thereby decreasing sympathetic renalnerve activity and decreasing central sympathetic drive. Selective renalneuromodulation may be repeated one or more times at various intervalsuntil a desired sympathetic nerve activity level or another therapeuticbenchmark is reached. In one embodiment, for example, a decrease insympathetic nerve activity may be observed via a marker of sympatheticnerve activity in patients, such as decreased levels of plasmanorepinephrine (noradrenaline). Other measures or markers of sympatheticnerve activity can include MSNA, norepinephrine spillover, and/or heartrate variability. In another embodiment, other measurable physiologicalparameters or markers, such as improved blood pressure control, improvedblood glucose regulation, etc., can be used to assess efficacy of thethermal modulation treatment for patients.

In certain embodiments of the methods provided herein, selective renalneuromodulation is expected to result in a change in sympathetic nerveactivity over a specific timeframe. For example, in certain of theseembodiments, sympathetic nerve activity levels are decreased over anextended timeframe, e.g., within 1 month, 2 months, 3 months, 6 months,9 months or 12 months post-neuromodulation.

In several embodiments, the methods disclosed herein may comprise anadditional step of measuring sympathetic nerve activity levels, and incertain of these embodiments, the methods can further comprise comparingthe activity level to a baseline activity level. Such comparisons can beused to monitor therapeutic efficacy and to determine when and if torepeat the neuromodulation procedure. In certain embodiments, a baselinesympathetic nerve activity level is derived from the subject undergoingtreatment. For example, baseline sympathetic nerve activity level may bemeasured in the subject at one or more timepoints prior to treatment. Abaseline sympathetic nerve activity value may represent sympatheticnerve activity at a specific timepoint before neuromodulation, or it mayrepresent an average activity level at two or more timepoints prior toneuromodulation. In certain embodiments, the baseline value is based onsympathetic nerve activity immediately prior to treatment (e.g., afterthe subject has already been catheterized). Alternatively, a baselinevalue may be derived from a standard value for sympathetic nerveactivity observed across the population as a whole or across aparticular subpopulation. In certain embodiments, post-neuromodulationsympathetic nerve activity levels are measured in extended timeframespost-neuromodulation, e.g., 3 months, 6 months or 12 monthspost-neuromodulation.

In certain embodiments of the methods provided herein, the methods aredesigned to decrease sympathetic nerve activity to a target level. Inthese embodiments, the methods include a step of measuring sympatheticnerve activity levels post-neuromodulation (e.g., 6 monthspost-treatment, 12 months post-treatment, etc.) and comparing theresultant activity level to a baseline activity level as discussedabove. In certain of these embodiments, the treatment is repeated untilthe target sympathetic nerve activity level is reached. In otherembodiments, the methods are simply designed to decrease sympatheticnerve activity below a baseline level without requiring a particulartarget activity level.

In addition to affecting the sympathetic nerve activity or centralsympathetic drive in a patient, selective renal neuromodulation (e.g.,selective afferent or selective efferent renal neuromodulation) mayefficaciously treat other measurable physiological parameter(s) orsequela corresponding to overactivity or hyperactivity of centralsympathetic drive. For example, in some embodiments, selective renalneuromodulation may address metabolic issues (e.g., obesity, metabolicsyndrome, insulin resistance), cardiovascular risk (e.g., highcholesterol, hypertension, LVH) and endocrine issues (e.g., sequelaassociated with polycystic ovary syndrome, erectile dysfunction). Theseand other results can occur at various times, e.g., directly followingselective renal neuromodulation or within about 1 month, 3 months, 6months, a year, or a longer period following selective renalneuromodulation.

As discussed previously, the progression of many cardiovascular,metabolic and/or endocrine disease states may be related to sympatheticoveractivity and, correspondingly, the degree of sympathoexcitation in apatient may be related to the severity of the clinical presentation ofthe respective conditions. The kidneys can be both a cause (directly viaafferent nerve fibers and indirectly via efferent nerve fibers) and atarget (via efferent sympathetic nerves) of elevated central sympatheticdrive. In some embodiments, selective renal neuromodulation can be usedto reduce central sympathetic drive in a patient in a manner that treatsthe patient for the disease state (e.g., cardiovascular, metabolic,endocrine, etc.). In some embodiments, for example, MSNA can be reducedby at least about 5%, about 10%, or about 20% in the patient withinabout three months after at least partially inhibiting sympatheticneural activity in afferent nerves proximate a renal pelvis, aureteropelvic junction, a major calyx, a minor calyx, and/or othersuitable structure. Similarly, in some instances whole bodynorepinephrine spillover to plasma can be reduced at least about 20% inthe patient within about three months after at least partiallyinhibiting sympathetic neural activity in afferent nerves proximate arenal pelvis, a ureteropelvic junction, a major calyx, a minor calyx,and/or other suitable structure. In another embodiment, MSNA can bereduced by at least about 5%, about 10%, or about 20% in the patientwithin about three months after at least partially inhibitingsympathetic neural activity in efferent nerves proximate a renal arteryand/or a renal branch artery, and/or another suitable structure.Similarly, whole body norepinephrine spillover to plasma can be reducedat least about 20% in the patient within about three months after atleast partially inhibiting sympathetic neural activity in efferentnerves proximate a renal artery and/or a renal branch artery, and/oranother suitable structure. Additionally, measured renal norepinephrinecontent (e.g., assessed via biopsy, assessed in real-time viaintravascular blood collection techniques, etc.) can be reduced (e.g.,at least about 5%, 10%, or by at least 20%) in the patient within aboutthree months after at least partially inhibiting sympathetic neuralactivity in efferent nerves proximate a renal artery innervating thekidney.

In one prophetic example, a patient diagnosed or suspected as havingsympathetic overactivity can be subjected to a baseline assessmentindicating a first set of measurable parameters corresponding tosympathetic overactivity. Such parameters can include, for example,blood pressure, cholesterol levels, blood glucose levels, fasting bloodinsulin levels, measures of insulin sensitivity, and aldosterone levels.Following baseline assessment, the patient can be subjected to aselective renal neuromodulation procedure (e.g., selective afferentneuromodulation, selective efferent neuromodulation). Such a procedurecan, for example, include any of the treatment modalities describedherein or another treatment modality in accordance with the presenttechnology. The treatment can be performed on afferent or efferentnerves innervating one or both kidneys of the patient. Following thetreatment (e.g., 1, 3, 6, or 12 months following the treatment), thepatient can be subjected to a follow-up assessment. The follow-upassessment can indicate a measurable improvement in one or morephysiological parameters corresponding to the sympathetic overactivity.

The methods described herein address the sympathetic excess that isthought to be an underlying cause or a central mechanism through whichdiseased or damaged kidneys manifests their multiple deleterious effectson patients. In contrast, known therapies currently prescribed for thispatient population typically address only specific manifestations of thevarious sequelae. Additionally, these known therapies can havesignificant limitations including limited efficacy, undesirable sideeffects and can be subject to adverse or undesirable drug interactionswhen used in combination. Additionally, conventional therapies requirethe patient to remain compliant with the treatment regimen over time. Incontrast, selective renal neuromodulation can be a one-time treatmentthat would be expected to have durable benefits to inhibit long-termdisease progression and thereby achieve a favorable patient outcome.

In some embodiments, patients diagnosed with sympathetic overactivityand/or diseased or damaged kidneys can be treated with selective renalneuromodulation alone. However, in other embodiments, these patients canbe treated with combinations of therapies for treating both primarycausative modes as well as sequelae of the cardiovascular, metabolicand/or endocrine related conditions. For example, combinations oftherapies can be tailored based on specific manifestations of thedisease in a particular patient. In a specific example, patients havingelevated or overactive sympathetic drive and presenting hypertension canbe treated with both anti-hypertensive therapy (e.g., drugs) andselective renal neuromodulation. In another example, selective renalneuromodulation can be combined with cholesterol lowering agents (e.g.,statins), hormonal therapy (e.g., estrogen-progestin contraceptive), andphosphodiesterase type 5 (PDE5) inhibitors (e.g., sildenafil, tadalafil,vardenafil, avanafil, etc.) as well as weight loss and lifestyle changerecommendations/programs.

Treatment of conditions relating to or resulting from sympatheticoveractivity may refer to preventing the condition, slowing the onset orrate of development of the condition, reducing the risk of developingthe condition, preventing or delaying the development of symptomsassociated with the condition, reducing or ending symptoms associatedwith the condition, generating a complete or partial regression of thecondition, or some combination thereof.

FIG. 7 is a block diagram illustrating a method 700 of selectivelymodulating afferent renal nerves using the system 100 described abovewith reference to FIGS. 1-4. With reference to FIGS. 1-4 and 7 together,the method 700 can optionally include selecting a suitable candidatepatient for performing selective afferent renal neuromodulation (block702). The method 700 can include locating the therapeutic element 302 ina delivery state (e.g., low-profile configuration) at a first targetsite in or near a first renal pelvis, a ureteropelvic junction, a majorcalyx, or a minor calyx (e.g., first renal pelvis or first renal calyx)(block 705). The first treatment device 102 and/or portions thereof(e.g., the therapeutic element 302) can be inserted into a guidecatheter or sheath to facilitate delivery of the therapeutic element 302through a ureter connected to the renal pelvis. In certain embodiments,for example, the first treatment device 102 can be configured to fitwithin an 8 Fr guide catheter or smaller (e.g., 7 Fr, 6 Fr, etc.) toaccess the ureter, the renal pelvis anatomy and/or renal calyces. Aguide wire (not shown), if present, can be used to manipulate andenhance control of the shaft 300 and the therapeutic element 302 (e.g.,in an over-the-wire or a rapid-exchange configuration). In someembodiments, radiopaque markers and/or markings on the first treatmentdevice 102 and/or the guide wire can facilitate placement of thetherapeutic element 302 at the first target site (e.g., first renalpelvis or first renal calyx of a patient). In some embodiments, acontrast material can be delivered distally beyond the therapeuticelement 302, and fluoroscopy and/or other suitable imaging techniquescan be used to aid in placement of the therapeutic element 302 at thefirst target site.

The method 700 can further include connecting the first treatment device102 to the console 106 (block 710), and determining whether thetherapeutic element 302 is in the correct position at the target siteand/or whether the therapeutic element (e.g., electrodes, transducers orcryotherapy balloon) is functioning properly (block 715). Once thetherapeutic element 302 is properly located at the first target site andno malfunctions are detected, the console 106 can be manipulated toinitiate application of an energy field to the target site to causeelectrically-induced and/or thermally-induced neuromodulation ofafferent nerve fibers innervating the kidney (e.g., using electrodes,transducers, or cryotherapeutic devices). Accordingly, heating and/orcooling of the therapeutic element 302 causes modulation of afferentrenal nerves at the first target site (block 720).

The therapeutic element 302 can then be located at a second target sitein or near a second renal pelvis, a ureteropelvic junction, a majorcalyx, or a minor calyx (e.g., second renal pelvis or second renalcalyx) (block 725), and correct positioning of the therapeutic element302 can be determined (block 730). In selected embodiments, a contrastmaterial can be delivered distally beyond the therapeutic element 302and fluoroscopy and/or other suitable imaging techniques can be used tolocate the second renal pelvis or second renal calyx. The method 700continues by applying targeted heat or cold to effectuate afferent renalneuromodulation at the second target site (block 735).

After providing the therapeutically-effective neuromodulation energy(e.g., cryogenic cooling, RF energy, ultrasound energy, etc.), themethod 700 may also include determining whether the neuromodulationtherapeutically treated the patient for one or more conditionsassociated with sympathetic overactivity or otherwise sufficientlymodulated afferent nerves or other neural structures proximate the firstand second target sites (block 740). For example, the process ofdetermining whether the neuromodulation therapeutically treated thenerves can include determining whether nerves were sufficientlymodulated or otherwise disrupted to reduce, suppress, inhibit, block orotherwise affect the afferent (and/or efferent) renal signals (e.g., byevaluation of suitable biomarkers, stimulation and recording of nervesignals, etc.). In a further embodiment, patient assessment could beperformed at time intervals (e.g., 1 month, 3 months, 6 months, 12months) following neuromodulation treatment. For example, the patientcan be assessed for measurements of perceived pain, blood pressurecontrol, blood glucose levels, and measures of sympathetic activity(e.g., MSNA, and/or renal norepinephrine spillover to plasma, whole bodynorepinephrine spillover, and heart rate variability).

FIG. 8 is another block diagram illustrating a method 800 of selectivelymodulating efferent renal nerves using the system 100 described abovewith reference to FIGS. 1 and 2 and FIGS. 5 and 6. With reference toFIGS. 1 and 2 and FIGS. 5-8 together, the method 800 can optionallyinclude selecting a suitable candidate patient for performing, selectiveefferent renal neuromodulation (block 802). In one embodiment, thepatient has systemic sympathetic overactivity or hyperactivity and isdiagnosed with cystinuria. In another embodiment, the patient hassystemic sympathetic overactivity or hyperactivity and has beendiagnosed as having an increased risk of developing kidney stonesrelative to the general population. The method 800 can includeintravascularly locating the therapeutic element 502 in a delivery state(e.g., low-profile configuration) at a first target site in or near afirst renal blood vessel (e.g., a first renal artery, a first renalbranch artery) or a first renal ostium (block 805). The first treatmentdevice 102 and/or portions thereof (e.g., the therapeutic element 502)can be inserted into a guide catheter or sheath to facilitateintravascular delivery of the therapeutic element 502. In certainembodiments, for example, the first treatment device 102 can beconfigured to fit within an 8 Fr guide catheter or smaller (e.g., 7 Fr,6 Fr, etc.) to access the ureter, the renal pelvis anatomy and/or renalcalyces). A guide wire (not shown), if present, can be used tomanipulate and enhance control of the shaft 500 and the therapeuticelement 502 (e.g., in an over-the-wire or a rapid-exchangeconfiguration). Radiopaque markers and/or markings on the firsttreatment device 102 and/or the guide wire can, in some embodiments,facilitate placement of the therapeutic element 502 at the first targetsite (e.g., first renal artery or branch artery or a first renal ostiumof a patient). In some embodiments, a contrast material can be delivereddistally beyond the therapeutic element 502, and fluoroscopy and/orother suitable imaging techniques can be used to aid in placement of thetherapeutic element 502 at the first target site.

The method 800 can further include connecting the first treatment device102 to the console 106 (block 810). Further steps can includedetermining whether the therapeutic element 502 is in the correctposition at the first target site and/or whether the therapeutic element502 (e.g., electrodes, transducers or cryotherapy balloon) is properlyfunctioning (block 815). Once the therapeutic element 502 is located atthe first target site and no malfunctions are detected, the console 106can be manipulated to initiate application of an energy field (e.g.,using a suitable algorithm) to the first target site to causeelectrically-induced and/or thermally-induced neuromodulation ofefferent nerve fibers innervating the kidney (e.g., using electrodes,transducers or cryotherapeutic devices). Accordingly, heating and/orcooling of the therapeutic element 502 causes modulation of efferentrenal nerves at the first target site (block 820).

If desirable, the therapeutic element 502 can be located at a secondtarget site in or near a second renal blood vessel (e.g., second renalartery, second renal branch artery or second renal ostium) (block 825),and correct positioning of the therapeutic element 502 can be determined(block 830). In selected embodiments, a contrast material can bedelivered distally beyond the therapeutic element 502 and fluoroscopyand/or other suitable imaging techniques can be used to locate thesecond renal artery, second renal branch artery or second renal ostium.The method 800 continues by applying targeted thermal energy toeffectuate efferent renal neuromodulation at the second target site(block 835).

After providing the therapeutically-effective neuromodulation energy(e.g., cryogenic cooling, RF energy, ultrasound energy, etc.), themethod 800 may also include determining whether the neuromodulationtherapeutically treated the patient for one or more conditionsassociated with sympathetic overactivity or otherwise sufficientlymodulated efferent nerves or other neural structures proximate the firstand/or second target sites (block 840). For example, the process ofdetermining whether the neuromodulation therapeutically treated theefferent nerves can include determining whether nerves were sufficientlymodulated or otherwise disrupted to reduce, suppress, inhibit, block orotherwise affect the efferent (and/or afferent) renal signals (e.g., byevaluation of suitable biomarkers, stimulation and recording of nervesignals, etc.). In a further embodiment, patient assessment could beperformed at time intervals (e.g., 1 month, 3 months, 6 months, 12months) following neuromodulation treatment. For example, the patientcan be assessed for measurements of perceived pain, blood pressurecontrol, blood glucose levels, and measures of sympathetic activity(e.g., MSNA, and/or renal norepinephrine spillover to plasma, whole bodynorepinephrine spillover, and heart rate variability).

Referring to FIGS. 7 and 8 together and in one example, the firsttreatment device 102 can be an RF energy emitting device and RF energycan be delivered through energy delivery elements or electrodes to oneor more locations along the inner wall of the first target site forpredetermined periods of time (e.g., 120 seconds). In some embodiments,multiple treatments (e.g., 4-6) may be administered in both the firstand second target sites (e.g., in the left and right renal pelvis orrenal arteries to achieve a desired coverage). An objective of atreatment may be, for example, to heat tissue to a desired depth (e.g.,at least about 1.5 mm, at least about 2 mm, at least about 3 mm) to atemperature (e.g., about 65° C.) that would modulate one or more nervefibers associated with or adjacent to one or more lesions formed in thevessel wall. A clinical objective of the procedure typically is toneuromodulate a sufficient number of renal nerves (e.g., selectivelyefferent or afferent nerves) to cause a reduction in central sympatheticdrive and/or reduction in sympathetic tone or drive to the kidneyswithout, for example, disrupting renal function and while minimizingvessel trauma. If the objective of a treatment is met (e.g., tissue isheated to about 65° C. to a depth of about 1 mm to about 3 min) theprobability of modulating renal nerve tissue (e.g., altering nervefunction) is high. In some embodiments, a single neuromodulationtreatment procedure can provide for sufficient modulation of targetsympathetic nerves (e.g., modulation of a sufficient number of nervefibers) to provide a desired clinical outcome. In other embodiments,more than one treatment may be beneficial for modulating a desirednumber or volume of target sympathetic nerve fibers, and thereby achieveclinical success. In other embodiments, an objective may includereducing or eliminating target sympathetic nerve function completely.

In a specific example of using RF energy for renal nerve modulation, aclinician can commence treatment which causes the control algorithm 132(FIG. 1) to initiate instructions to the generator (not shown) togradually adjust its power output to a first power level (e.g., 5 watts)over a first time period (e.g., 15 seconds). The power increase duringthe first time period is generally linear. As a result, the generatorincreases its power output at a generally constant rate of power/time,i.e., in a linear manner. Alternatively, the power increase may benon-linear e.g., exponential or parabolic) with a variable rate ofincrease. Once the first power level and the first time are achieved,the algorithm may hold at the first power level until a secondpredetermined period of time has elapsed (e.g., 3 seconds). At theconclusion of the second period of time, power is again increased by apredetermined increment (e.g., 1 watt) to a second power level over athird predetermined period of time (e.g., 1 second). This power ramp inpredetermined increments of about 1 watt over predetermined periods oftime may continue until a maximum power P_(MAX) is achieved or someother condition is satisfied. In one embodiment, P_(MAX) is 8 watts. Inanother embodiment, P_(MAX) is 10 watts, or in a further embodiment,P_(MAX) is 6.5 watts. In some embodiments, P_(MAX) can be about 6 wattsto about 10 watts. Optionally, the power may be maintained at themaximum power P_(MAX) for a desired period of time or up to the desiredtotal treatment time (e.g., up to about 120 seconds) or until aspecified temperature is reached or maintained for a specified timeperiod.

In another specific example, the first treatment device 102 can be acryogenic device and cryogenic cooling can be applied for one or morecycles (e.g., for 30 second increments, 60 second increments, 90 secondincrements, etc.) in one or more locations along the circumferenceand/or length of the first target site. The cooling cycles can be, forexample, fixed periods or can be fully or partially dependent ondetected temperatures (e.g., temperatures detected by a thermocouple(not shown) of the therapeutic element 302 or 502). In some embodiments,a first stage can include cooling tissue until a first targettemperature is reached. A second stage can include maintaining coolingfor a set period, such as 15-180 seconds (e.g., 90 seconds). A thirdstage can include terminating or decreasing cooling to allow the tissueto warm to a second target temperature higher than the first targettemperature. A fourth stage can include continuing to allow the tissueto warm for a set period, such as 10-120 seconds (e.g., 60 seconds). Afifth stage can include cooling the tissue until the first targettemperature (or a different target temperature) is reached. A sixthstage can include maintaining cooling for a set period, such as 15-180seconds (e.g., 90 seconds). A seventh stage can, for example, includeallowing the tissue to warm completely (e.g., to reach a bodytemperature).

In other embodiments, various steps in the methods 700 or 800 can bemodified, omitted, and/or additional steps may be added. In furtherembodiments, the methods 700 or 800 can have a delay between applyingtherapeutically-effective neuromodulation energy at a first target siteand applying therapeutically-effective neuromodulation energy at asecond target site. For example, neuromodulation of the first targetsite can take place at a first treatment session, and neuromodulation ofthe second target site can take place at a second treatment session at alater time. In other embodiments, various steps of the methods 700 and800 could be combined. In a specific example, therapeutically-effectiveneuromodulation energy can be delivered at a first target site in arenal artery (e.g., energy delivered intravascularly by catheter), andtherapeutically-effective neuromodulation energy can be delivered (e.g.,either prior to, concurrently with, or following energy delivery to thefirst target site) at a second target site in a renal pelvis (e.g.,energy delivered via a catheterization path through the ureter and/ordelivered extracorporeally). Accordingly, embodiments of the methodsdisclosed herein include neuromodulation of nerves proximate to renalblood vessel(s) and/or the renal pelvis. Without being bound by theory,in some embodiments it is believed that modulation of nerves proximateboth the renal artery and the renal pelvis may provide for modulation ofa higher percentage of afferent nerve fibers with respect to a totalnumber of modulated nerve fibers.

As discussed previously, treatment procedures for selective modulationof afferent or efferent renal nerves in accordance with embodiments ofthe present technology are expected to improve at least one conditionassociated with renal sympathetic activity (e.g., overactivity orhyperactivity) and/or central sympathetic activity (e.g., overactivityor hyperactivity). For example, with respect to central sympatheticactivity (e.g., overactivity or hyperactivity), modulation of renalnerves is expected to reduce muscle sympathetic nerve activity and/orwhole body norepinephrine spillover in patients. These and otherclinical effects are expected to be detectable immediately after atreatment procedure or after a delay, e.g., of 1, 2, or 3 months. Insome instances, it may be useful to repeat selective renalneuromodulation, such as selective efferent or afferent renalneuromodulation, at the same treatment location or a different treatmentlocation after a suitable delay, e.g., 1, 2, or 3 years. In still otherembodiments, however, other suitable treatment regimens or techniquesmay be used.

VIII. PERTINENT ANATOMY AND PHYSIOLOGY

The following discussion provides further details regarding pertinentpatient anatomy and physiology. This section is intended to supplementand expand upon the previous discussion regarding the relevant anatomyand physiology, and to provide additional context regarding thedisclosed technology and the therapeutic benefits associated with renalneuromodulation. For example, as mentioned previously, severalproperties of the renal vasculature may inform the design of treatmentdevices and associated methods for achieving renal neuromodulation viaintravascular access, and impose specific design requirements for suchdevices. Specific design requirements may include accessing the renalartery, facilitating stable contact between the energy delivery elementsof such devices and a luminal surface or wall of the renal artery,and/or effectively modulating the renal nerves with the neuromodulatoryapparatus.

The Sympathetic Nervous System

The SNS is a branch of the autonomic nervous system along with theenteric nervous system and parasympathetic nervous system. It is alwaysactive at a basal level (called sympathetic tone) and becomes moreactive during times of stress. Like other parts of the nervous system,the SNS operates through a series of interconnected neurons. Sympatheticneurons are frequently considered part of the peripheral nervous system(PNS), although many lie within the central nervous system (CNS).Sympathetic neurons of the spinal cord (which is part of the CNS)communicate with peripheral sympathetic neurons via a series ofsympathetic ganglia. Within the ganglia, spinal cord sympathetic neuronsjoin peripheral sympathetic neurons through synapses. Spinal cordsympathetic neurons are therefore called presynaptic (or preganglionic)neurons, while peripheral sympathetic neurons are called postsynaptic(or postganglionic) neurons.

At synapses within the sympathetic ganglia, preganglionic sympatheticneurons release acetylcholine, a chemical messenger that binds andactivates nicotinic acetylcholine receptors on postganglionic neurons.In response to this stimulus, postganglionic neurons principally releasenoradrenaline (norepinephrine). Prolonged activation may elicit therelease of adrenaline from the adrenal medulla.

Once released, norepinephrine binds adrenergic receptors on peripheraltissues. Binding to adrenergic receptors causes a neuronal and hormonalresponse. The physiologic manifestations include pupil dilation,increased heart rate, occasional vomiting, and increased blood pressure.Increased sweating is also seen due to binding of cholinergic receptorsof the sweat glands.

The SNS is responsible for up-and down-regulation of many homeostaticmechanisms in living organisms. Fibers from the SNS innervate tissues inalmost every organ system, providing at least some regulatory functionto physiological features as diverse as pupil diameter, gut motility,and urinary output. This response is also known as the sympatho-adrenalresponse of the body, as the preganglionic sympathetic fibers that endin the adrenal medulla (but also all other sympathetic fibers) secreteacetylcholine, which activates the secretion of adrenaline (epinephrine)and to a lesser extent noradrenaline (norepinephrine). Therefore, thisresponse that acts primarily on the cardiovascular system is mediateddirectly via impulses transmitted through the SNS and indirectly viacatecholamines secreted from the adrenal medulla.

Science typically looks at the SNS as an automatic regulation system,that is, one that operates without the intervention of consciousthought. Some evolutionary theorists suggest that the SNS operated inearly organisms to maintain survival as the SNS is responsible forpriming the body for action. One example of this priming is in themoments before waking, in which sympathetic outflow spontaneouslyincreases in preparation for action.

1. The Sympathetic Chain

As shown in FIG. 9, the SNS provides a network of nerves that allows thebrain to communicate with the body. Sympathetic nerves originate insidethe vertebral column, toward the middle of the spinal cord in theintermediolateral cell column (or lateral horn), beginning at the firstthoracic segment of the spinal cord and are thought to extend to thesecond or third lumbar segments. Because its cells begin in the thoracicand lumbar regions of the spinal cord, the SNS is said to have athoracolumbar outflow. Axons of these nerves leave the spinal cordthrough the anterior rootlet/root. They pass near the spinal (sensory)ganglion, where they enter the anterior rami of the spinal nerves.However, unlike somatic innervation, they quickly separate out throughwhite rami connectors that connect to either the paravertebral (whichlie near the vertebral column) or prevertebral (which lie near theaortic bifurcation) ganglia extending alongside the spinal column.

In order to reach the target organs and glands, the axons travel longdistances in the body. Many axons relay their message to a second cellthrough synaptic transmission. The first cell (the presynaptic cell)sends a neurotransmitter across the synaptic cleft (the space betweenthe axon terminal of the first cell and the dendrite of the second cell)where it activates the second cell (the postsynaptic cell). The messageis then propagated to the final destination.

In the SNS and other neuronal networks of the peripheral nervous system,these synapses are located at sites called ganglia, discussed above. Thecell that sends its fiber to a ganglion is called a preganglionic cell,while the cell whose fiber leaves the ganglion is called apostganglionic cell. As mentioned previously, the preganglionic cells ofthe SNS are located between the first thoracic (T1) segment and thirdlumbar (L3) segments of the spinal cord. Postganglionic cells have theircell bodies in the ganglia and send their axons to target organs orglands. The ganglia include not just the sympathetic trunks but also thecervical ganglia (superior, middle and inferior), which sendssympathetic nerve fibers to the head and thorax organs, and the celiacand mesenteric ganglia (which send sympathetic fibers to the gut).

2. Nerves of the Kidneys

As FIG. 10 shows, the kidney is innervated by the renal plexus RP, whichis intimately associated with the renal artery RA. The renal plexus RPis an autonomic plexus that surrounds the renal artery RA and isembedded within the adventitia of the renal artery RA. The renal plexusRP extends along the renal artery RA until it arrives at the substanceof the kidney. Fibers contributing to the renal plexus RP arise from theceliac ganglion, the superior mesenteric ganglion, the aorticorenalganglion and the aortic plexus. The renal plexus RP, also referred to asthe renal nerve, is predominantly comprised of sympathetic components.There is no (or at least very minimal) parasympathetic innervation ofthe kidney.

Preganglionic neuronal cell bodies are located in the intermediolateralcell column of the spinal cord. Preganglionic axons pass through theparavertebral ganglia (they do not synapse) to become the lessersplanchnic nerve, the least splanchnic nerve, the first lumbarsplanchnic nerve, and the second lumbar splanchnic nerve, and theytravel to the celiac ganglion, the superior mesenteric ganglion, and theaorticorenal ganglion. Postganglionic neuronal cell bodies exit theceliac ganglion, the superior mesenteric ganglion, and the aorticorenalganglion to the renal plexus RP and are distributed to the renalvasculature.

3. Renal Sympathetic Neural Activity

Messages travel through the SNS in a bidirectional flow. Efferentmessages may trigger changes in different parts of the bodysimultaneously. For example, the sympathetic nervous system mayaccelerate heart rate, widen bronchial passages, decrease motility(movement) of the large intestine, constrict blood vessels, increaseperistalsis in the esophagus, cause pupil dilation, piloerection (goosebumps) and perspiration (sweating), and raise blood pressure. Afferentmessages carry signals from various organs and sensory receptors in thebody to other organs and, particularly, the brain.

Hypertension, heart failure and chronic kidney disease are a few of manydisease states that result from chronic activation of the SNS,especially the renal sympathetic nervous system. Chronic activation ofthe SNS is a maladaptive response that drives the progression of thesedisease states. Pharmaceutical management of therenin-angiotensin-aldosterone system (RAAS) has been a longstanding, butsomewhat ineffective, approach for reducing over-activity of the SNS.

As mentioned above, the renal sympathetic nervous system has beenidentified as a major contributor to the complex pathophysiology ofhypertension, states of volume overload (such as heart failure), andprogressive renal disease, both experimentally and in humans. Studiesemploying radiotracer dilution methodology to measure overflow ofnorepinephrine (NE) from the kidneys to plasma revealed increased renalNE spillover rates in patients with essential hypertension, particularlyso in young hypertensive subjects, which in concert with increased NEspillover from the heart, is consistent with the hemodynamic profiletypically seen in early hypertension and characterized by an increasedheart rate, cardiac output, and renovascular resistance. It is now knownthat essential hypertension is commonly neurogenic, often accompanied bypronounced SNS overactivity.

Activation of cardiorenal sympathetic nerve activity is even morepronounced in heart failure, as demonstrated by an exaggerated increaseof NE overflow from the heart and the kidneys to plasma in this patientgroup. In line with this notion is the recent demonstration of a strongnegative predictive value of renal sympathetic activation on all-causemortality and heart transplantation in patients with congestive heartfailure, which is independent of overall sympathetic activity,glomerular filtration rate, and left ventricular ejection fraction.These findings support the notion that treatment regimens that aredesigned to reduce renal sympathetic stimulation have the potential toimprove survival in patients with heart failure.

Both chronic and end stage renal disease are characterized by heightenedsympathetic nervous activation. In patients with end stage renaldisease, plasma levels of norepinephrine above the median have beendemonstrated to be predictive for both all-cause death and death fromcardiovascular disease. This is also true for patients suffering fromdiabetic or contrast nephropathy. There is compelling evidencesuggesting that sensory afferent signals originating from the diseasedkidneys are major contributors to initiating and sustaining elevatedcentral sympathetic outflow in this patient group; this facilitates theoccurrence of the well known adverse consequences of chronic sympatheticover activity, such as hypertension, left ventricular hypertrophy,ventricular arrhythmias, sudden cardiac death, insulin resistance,diabetes, and metabolic syndrome.

(i) Renal Sympathetic Efferent Activity

Sympathetic nerves to the kidneys terminate in the blood vessels, thejuxtaglomerular apparatus and the renal tubules. Stimulation of therenal sympathetic nerves causes increased renin release, increasedsodium (Na⁴⁰) reabsorption, and a reduction of renal blood flow. Thesecomponents of the neural regulation of renal function are considerablystimulated in disease states characterized by heightened sympathetictone and clearly contribute to the rise in blood pressure inhypertensive patients. The reduction of renal blood flow and glomerularfiltration rate as a result of renal sympathetic efferent stimulation islikely a cornerstone of the loss of renal function in cardio-renalsyndrome, which is renal dysfunction as a progressive complication ofchronic heart failure, with a clinical course that typically fluctuateswith the patient's clinical status and treatment. Pharmacologicstrategies to thwart the consequences of renal efferent sympatheticstimulation include centrally acting sympatholytic drugs, beta blockers(intended to reduce renin release), angiotensin converting enzymeinhibitors and receptor blockers (intended to block the action ofangiotensin II and aldosterone activation consequent to renin release)and diuretics (intended to counter the renal sympathetic mediated sodiumand water retention). However, the current pharmacologic strategies havesignificant limitations including limited efficacy, compliance issues,side effects and others.

(ii) Renal Sensory Afferent Nerve Activity

The kidneys communicate with integral structures in the CNS via renalsensory afferent nerves. Several forms of “renal injury” may induceactivation of sensory afferent signals. For example, renal ischemia,reduction in stroke volume or renal blood flow, or an abundance ofadenosine enzyme may trigger activation of afferent neuralcommunication. As shown in FIGS. 11B and 11B, this afferentcommunication might be from the kidney to the brain or might be from onekidney to the other kidney (via the CNS). These afferent signals arecentrally integrated and may result in increased sympathetic outflow.This sympathetic drive is directed towards the kidneys, therebyactivating the RAAS and inducing increased renin secretion, sodiumretention, volume retention and vasoconstriction. Central sympatheticoveractivity also impacts other organs and bodily structures innervatedby sympathetic nerves such as the heart and the peripheral vasculature,resulting in the described adverse effects of sympathetic activation,several aspects of which also contribute to the rise in blood pressure.

The physiology therefore suggests that (i) modulation of tissue withefferent sympathetic nerves will reduce inappropriate renin release,sodium retention, and reduction of renal blood flow, and that (ii)modulation of tissue with afferent sensory nerves will reduce thesystemic contribution to hypertension and other disease statesassociated with increased central sympathetic tone through its directeffect on the posterior hypothalamus as well as the contralateralkidney. In addition to the central hypotensive effects of afferent renalneuromodulation, a desirable reduction of central sympathetic outflow tovarious other organs such as the heart and the vasculature isanticipated.

B. Additional Clinical Benefits of Renal Neuromodulation

As provided above, selective and/or non-selective renal neuromodulationis likely to be valuable in the treatment of several clinical conditionscharacterized by increased overall and particularly renal sympatheticactivity such as hypertension, metabolic syndrome, insulin resistance,diabetes, left ventricular hypertrophy, chronic end stage renal disease,inappropriate fluid retention in heart failure, cardio-renal syndrome,and sudden death. Since the reduction of afferent neural signalscontributes to the systemic reduction of sympathetic tone/drive, renalneuromodulation and, in one embodiment, selective afferent renalneuromodulation might also be useful in treating other conditionsassociated with systemic sympathetic hyperactivity. Accordingly,selective and/or non-selective renal neuromodulation may also benefitother organs and bodily structures having sympathetic nerves, includingthose identified in FIG. 9. For example, as previously discussed, areduction in central sympathetic drive may reduce the insulin resistancethat afflicts people with metabolic syndrome and Type II diabetics.Additionally, patients with osteoporosis are also sympatheticallyactivated and might also benefit from the down regulation of sympatheticdrive that accompanies renal denervation.

C. Achieving Intravascular Access to the Renal Artery

In accordance with the present technology, neuromodulation of a leftand/or right renal plexus RP, which is intimately associated with a leftand/or right renal artery, may be achieved through intravascular access.As FIG. 12A shows, blood moved by contractions of the heart is conveyedfrom the left ventricle of the heart by the aorta. The aorta descendsthrough the thorax and branches into the left and right renal arteries.Below the renal arteries, the aorta bifurcates at the left and rightiliac arteries. The left and right iliac arteries descend, respectively,through the left and right legs and join the left and right femoralarteries.

As FIG. 12B shows, the blood collects in veins and returns to the heart,through the femoral veins into the iliac veins and into the inferiorvena cava. The inferior vena cava branches into the left and right renalveins. Above the renal veins, the inferior vena cava ascends to conveyblood into the right atrium of the heart. From the right atrium, theblood is pumped through the right ventricle into the lungs, where it isoxygenated. From the lungs, the oxygenated blood is conveyed into theleft atrium. From the left atrium, the oxygenated blood is conveyed bythe left ventricle back to the aorta.

As will be described in greater detail later, the femoral artery may beaccessed and cannulated at the base of the femoral triangle justinferior to the midpoint of the inguinal ligament. A catheter (notshown) may be inserted percutaneously into the femoral artery throughthis access site, passed through the iliac artery and aorta, and placedinto either the left or right renal artery. This route comprises anintravascular path that offers minimally invasive access to a respectiverenal artery and/or other renal blood vessels.

The wrist, upper arm, and shoulder region provide other locations forintroduction of catheters into the arterial system. For example,catheterization of either the radial, brachial, or axillary artery maybe utilized in select cases. Catheters introduced via these accesspoints may be passed through the subclavian artery on the left side (orvia the subclavian and brachiocephalic arteries on the right side),through the aortic arch, down the descending aorta and into the renalarteries using standard angiographic technique.

D. Properties and Characteristics of the Renal Vasculature

Properties and characteristics of the renal vasculature imposechallenges to both access and treatment methods, and to system/devicedesigns. Since neuromodulation of a left and/or right renal plexus RPmay be achieved in accordance with embodiments of the present technologythrough intravascular access, various aspects of the design ofapparatus, systems, and methods for achieving such renal neuromodulationare disclosed herein. Aspects of the technology disclosed herein addressadditional challenges associated with variation of physiologicalconditions and architecture across the patient population and/or withina specific patient across time, as well as in response to diseasestates, such as hypertension, chronic kidney disease, vascular disease,end-stage renal disease, insulin resistance, diabetes, metabolicsyndrome, etc. For example, the design of the intravascular device andtreatment protocols can address not only material/mechanical, spatial,fluid dynamic/hemodynamic and/or thermodynamic properties, but alsoprovide particular algorithms and feedback protocols for deliveringenergy and obtaining real-time confirmatory results of successfullydelivering energy to an intended target location in a patient-specificmanner.

As discussed previously, a catheter may be advanced percutaneously intoeither the left or right renal artery via a minimally invasiveintravascular path. However, minimally invasive renal arterial accessmay be challenging, for example, because as compared to some otherarteries that are routinely accessed using catheters, the renal arteriesare often extremely tortuous, may be of relatively small diameter,and/or may be of relatively short length. Furthermore, renal arterialatherosclerosis is common in many patients, particularly those withcardiovascular disease. Renal arterial anatomy also may varysignificantly from patient to patient, which further complicatesminimally invasive access. Significant inter-patient variation may beseen, for example, in relative tortuosity, diameter, length, and/oratherosclerotic plaque burden, as well as in the take-off angle at whicha renal artery branches from the aorta. Apparatus, systems and methodsfor achieving renal neuromodulation via intravascular access shouldaccount for these and other aspects of renal arterial anatomy and itsvariation across the patient population when minimally invasivelyaccessing a renal artery. For example, spiral or helical computedtomography (CT) technology can be used to produce 3D images of thevascular features for individual patients, and intravascular path choiceas well as device size/diameter, length, flexibility, torque-ability,kink resistance, etc. can be selected based upon the patient's specificvascular features.

In addition to complicating renal arterial access, specifics of therenal anatomy also complicate establishment of stable contact betweenneuromodulatory apparatus and a luminal surface or wall of a renalartery. When the neuromodulatory apparatus includes an energy deliveryelement, such as an electrode, transducer, heating element or acryotherapeutic device, consistent positioning and appropriate contactforce applied by the energy or cryotherapy delivery element to thevessel wall, and adhesion between the applicator and the vessel wall canbe important for predictability. However, navigation can be impeded bythe tight space within a renal artery RA, as well as tortuosity of theartery. Furthermore, establishing consistent contact can be complicatedby patient movement, respiration, and/or the cardiac cycle because thesefactors may cause significant movement of the renal artery RA relativeto the aorta, and the cardiac cycle may transiently distend the renalartery RA (i.e., cause the wall of the artery to pulse). As mentionedpreviously, to address these challenges, the treatment device orapplicator may be designed with relative sizing and flexibilityconsiderations. For example, the renal artery may have an internaldiameter in a range of about 2-10 mm and the treatment device can bedelivered using a 3, 4, 5, 6, 7 French, or in some cases, an 8 Frenchsized catheter. To address challenges associated with patient and/orarterial movement during treatment, the treatment device andneuromodulation system can be configured to use sensory feedback, suchas impedance and temperature, to detect instability and to alert theoperator to reposition the device and/or to temporarily stop treatment.In other embodiments, energy delivery algorithms can be varied inreal-time to account for changes detected due to patient and/or arterialmovement. In further examples, the treatment device may include one ormore modifications or movement resistant enhancements such as atraumaticfriction knobs or barbs on an outside surface of the device forresisting movement of the device relative to the desired tissuelocation, positionable balloons for inflating and holding the device ina consistent and stable position during treatment, or the device caninclude a cryogenic component that can temporarily freeze or adhere thedevice to the desired tissue location.

After accessing a renal artery and facilitating stable contact betweenneuromodulatory apparatus and a luminal surface of the artery, nerves inand around the adventitia of the artery can be modulated via theneuromodulatory apparatus. Effectively applying thermal treatment fromwithin a renal artery is non-trivial given the potential clinicalcomplications associated with such treatment. For example, the intimaand media of the renal artery are highly vulnerable to thermal injury.As discussed in greater detail below, the intima-media thicknessseparating the vessel lumen from its adventitia means that target renalnerves may be multiple millimeters distant (e.g., 1-3 mm) from theluminal surface of the artery. Sufficient energy can be delivered to thetarget renal nerves to modulate the target renal nerves withoutexcessively cooling or heating the vessel wall to the extent that thewall is frozen, desiccated, or otherwise potentially affected to anundesirable extent. For example, when employing energy modalities suchas RF or ultrasound, energy delivery can be focused on a locationfurther from the interior vessel wall. In one embodiment, the majorityof the RF or ultrasound energy can be focused on a location (e.g., a“hot spot”) 1-3 mm beyond the interior surface of the vessel wall. Theenergy will dissipate from the hot spot in a radially decreasing manner.Thus, the targeted nerves can be modulated without damage to the luminalsurface of the vessel. A potential clinical complication associated withexcessive heating is thrombus formation from coagulating blood flowingthrough the artery. Given that this thrombus may cause a kidney infarct,thereby causing irreversible damage to the kidney, thermal treatmentfrom within the renal artery RA can be applied carefully. Accordingly,the complex fluid mechanics and thermodynamic conditions present in therenal artery during treatment, particularly those that may impact heattransfer dynamics at the treatment site, may be important in applyingenergy (e.g., heating thermal energy) and/or removing heat from thetissue (e.g., cooling thermal conditions) from within the renal artery.

The neuromodulatory apparatus can also be configured to allow foradjustable positioning and repositioning of an energy delivery elementor a cryotherapeutic device, within the renal artery since location oftreatment may also impact clinical efficacy. For example, it may betempting to apply a full circumferential treatment from within the renalartery given that the renal nerves may be spaced circumferentiallyaround a renal artery. In some situations, a full-circle lesion likelyresulting from a continuous circumferential treatment may be potentiallyrelated to renal artery stenosis. Therefore, the formation of morecomplex lesions along a longitudinal dimension of the renal artery viathe cryotherapeutic devices or energy delivery elements and/orrepositioning of the neuromodulatory apparatus to multiple treatmentlocations may be desirable. It should be noted, however, that a benefitof forming a circumferential lesion or ablation may outweigh thepotential of renal artery stenosis or the risk may be mitigated withcertain embodiments or in certain patients and forming a circumferentiallesion or ablation could be a goal. Additionally, variable positioningand repositioning of the neuromodulatory apparatus may prove to beuseful in circumstances where the renal artery is particularly tortuousor where there are proximal branch vessels off the renal artery mainvessel, making treatment in certain locations challenging.

Blood flow through a renal artery may be temporarily occluded for ashort time with minimal or no complications. However, occlusion for asignificant amount of time can be avoided in some cases to preventinjury to the kidney such as ischemia. It can be beneficial to avoidocclusion altogether or, if occlusion is beneficial, to limit theduration of occlusion (e.g., 2-5 minutes).

Based on the above described challenges of (1) renal arteryintervention, (2) consistent and stable placement of the treatmentelement against the vessel wall, (3) effective application of treatmentacross the vessel wall, (4) positioning and potentially repositioningthe treatment apparatus to allow for multiple treatment locations, and(5) avoiding or limiting duration of blood flow occlusion, variousindependent and dependent properties of the renal vasculature that maybe of interest include, for example, (a) vessel diameter, vessel length,intima-media thickness, coefficient of friction, and tortuosity; (b)distensibility, stiffness and modulus of elasticity of the vessel wall;(c) peak systolic, end-diastolic blood flow velocity, as well as themean systolic-diastolic peak blood flow velocity, and mean/maxvolumetric blood flow rate; (d) specific heat capacity of blood and/orof the vessel wall, thermal conductivity of blood and/or of the vesselwall, and/or thermal convectivity of blood flow past a vessel walltreatment site and/or radiative heat transfer; (e) renal artery motionrelative to the aorta induced by respiration, patient movement, and/orblood flow pulsatility; and (f) the takeoff angle of a renal arteryrelative to the aorta. These properties will be discussed in greaterdetail with respect to the renal arteries. However, depending on theapparatus, systems, and methods utilized to achieve renalneuromodulation, such properties of the renal arteries also may guideand/or constrain design characteristics.

As noted above, an apparatus positioned within a renal artery canconform to the geometry of the artery. Renal artery vessel diameter,D_(RA), typically is in a range of about 2-10 mm, with most of thepatient population having a D_(RA) of about 4 mm to about 8 mm and anaverage of about 6 mm. Renal artery vessel length, L_(RA), between itsostium at the aorta/renal artery juncture and its distal branchings,generally is in a range of about 5-70 mm, and a significant portion ofthe patient population is in a range of about 20-50 mm. Since the targetrenal plexus is embedded within the adventitia of the renal artery, thecomposite intima-media thickness, IMT, (i.e., the radial outwarddistance from the artery's luminal surface to the adventitia containingtarget neural structures) also is notable and generally is in a range ofabout 0.5-2.5 mm, with an average of about 1.5 mm. Although a certaindepth of treatment can be important to reach the target neural fibers,the treatment typically is not too deep (e.g., the treatment can be lessthan about 5 mm from the inner wall of the renal artery) so as to avoidnon-target tissue and anatomical structures such as the renal vein.

An additional property of the renal artery that may be of interest isthe degree of renal motion relative to the aorta, induced by respirationand/or blood flow pulsatility. A patient's kidney, which is located atthe distal end of the renal artery, may move as much as four inchescranially with respiratory excursion. This may impart significant motionto the renal artery connecting the aorta and the kidney. Accordingly,the neuromodulatory apparatus can have a unique balance of stiffness andflexibility to maintain contact between a cryo-applicator or anotherthermal treatment element and the vessel wall during cycles ofrespiration. Furthermore, the takeoff angle between the renal artery andthe aorta may vary significantly between patients, and also may varydynamically within a patient, e.g., due to kidney motion. The takeoffangle generally may be in a range of about 30°-135°.

IX. EXAMPLES Example 1: Effect of Renal Neuromodulation on Hypertension

Patients selected having a baseline systolic blood pressure of 160 mm Hgor more (2: 150 mm Hg for patients with type 2 diabetes) and takingthree or more antihypertensive drugs, were randomly allocated into twogroups: 51 assessed in a control group (antihypertensive drugs only) and49 assessed in a treated group (undergone renal neuromodulation andantihypertensive drugs).

Patients in both groups were assessed at 6 months. Office-based bloodpressure measurements in the treated group were reduced by 32/12 mm Hg(SD 23/11, baseline of 178/96 mm Hg, p<0,0001), whereas they did notdiffer from baseline in the control group (change of 1/0 mm Hg, baselineof 178/97 mm Hg, p=0.77 systolic and p=0.83 diastolic). Between-groupdifferences in blood pressure at 6 months were 33/11 min Hg (p<0.0001).At 6 months, 41 (84%) of 49 patients who underwent renal neuromodulationhad a reduction in systolic blood pressure of 10 mm Hg or more, comparedwith 18 (35%) of 51 control patients (p<0.0001).

Example 2: Effect of Renal Neuromodulation on Components of the RAAS inPatients with Resistant Hypertension

Eight patients (55.4±13 years) with treatment resistant hypertensionwere included in a study to determine blood and urine samples levels ofindividual components of the renin-angiotensin-aldosterone system (RAAS)before (day −1), after (day=1) and again after 3 months of renal nerveablation.

Results indicated no statistically significant change in renal plasmaflow, plasma renin activity or serum angiotensin II levels in thiscohort of patients. There was a significant acute decrease in plasmaaldosterone concentration one day post ablation (day −1: 161 (140-265)vs. day +1: 110 (101-168) pg/ml, p=0.012) and in accordance an increasedurinary sodium/potassium ratio (day −1: 2.41 (1.17-3.44) vs. day +1:6.02 (4.83-7.92), p=0.028). After 3 months, these changes were no longerevident. Urinary angiotensinogen levels, considered as a parameter ofthe local renal RAAS activity, tended to be reduced at day +1 (P=0.116)and significantly decreased after 3 months (6.06 (3.02−13.8) vs. 16.6(8.50-37.0). P=0.046 compared to day −1 levels.

X. FURTHER EXAMPLES

1. A method for treating a human patient, comprising:

-   -   selectively neuromodulating afferent renal nerves in the patient        compared to efferent renal nerves in the patient; and    -   improving a measurable physiological parameter in the patient        corresponding to systemic sympathetic overactivity or        hyperactivity.

2. The method of example 1, further comprising reducing musclesympathetic nerve activity at least about 10% in the patient withinabout three months after selectively neuromodulating the afferent renalnerves.

3. The method of example 1 or example 2, further comprising reducingwhole body norepinephrine spillover in the patient.

4. The method of any one of examples 1-3, further comprising reducingwhole body norepinephrine spillover at least about 20% in the patientwithin about three months after selectively neuromodulating the afferentrenal nerves.

5. A method for treating a human patient having a diagnosed condition ordisease associated with systemic sympathetic overactivity, the methodcomprising:

-   -   activating a medium within a renal pelvis of a kidney of the        patient; and    -   at least partially inhibiting sympathetic neural activity in        nerves proximate the renal pelvis via the medium.

6. The method of example 5 wherein

-   -   the medium includes a fluid,    -   the method further comprises introducing the fluid into the        renal pelvis, and    -   activating the medium selectively affects afferent renal nerves        compared to efferent renal nerves in the patient.

7. The method of example 5 or example 6, further comprising at leastpartially blocking the ureter to at least partially maintain the mediumin the renal pelvis.

8. The method of any one of examples 5-7 wherein activating the mediumincludes heating the medium to a temperature sufficient to at leastpartially inhibit sympathetic neural activity in the nerves.

9. The method of example 8 wherein heating the medium includes applyingultrasound energy to the medium.

10. The method of example 8 or example 9 wherein heating the mediumincludes focusing ultrasound energy in a focal zone within the medium.

11. The method of example 8 or example 9 wherein the medium is selectedto preferentially heat in the presence of the ultrasound energy relativeto tissue surrounding the renal pelvis.

12. The method of example 8 or example 9 wherein the medium includes amicrobubble contrast agent.

13. The method of any one of examples 5-12, further comprising

-   -   introducing a catheter through a ureter connected to the renal        pelvis; and    -   positioning a therapeutic element of the catheter within the        renal pelvis.

14. The method of example 13, further comprising activating the mediumusing the therapeutic element.

15. The method of example 13 or example 14 wherein the therapeuticelement includes one or more electrodes configured to deliveryradiofrequency energy.

16. The method of example 13 or example 14 wherein the therapeuticelement includes a cryotherapeutic cooling assembly.

17. The method of example 13 or example 14 wherein the therapeuticelement is configured to deliver microwave energy.

18. The method of example 13 or example 14 wherein the therapeuticelement is configured to deliver direct heat.

19. The method of any one of examples 13-18, wherein the therapeuticelement includes an opening, and wherein activating the medium includesintroducing a chemical into the medium via the opening.

20. The method of example 19, wherein the therapeutic element includesan electrode, and wherein activating the medium further comprisesactivating the electrode to move at least a portion of the chemical intoa wall of the renal pelvis by electrophoresis.

21. A method for treating a human patient, comprising:

-   -   focusing ultrasound energy in a focal zone along a renal pelvic        wall of a kidney of the patient; and    -   at least partially inhibiting sympathetic neural activity in        nerves proximate the renal pelvic wall.

22. The method of example 21, further comprising introducing a fluidinto the renal pelvis.

23. The method of example 22, further comprising

-   -   introducing a catheter through a ureter of the patient; and    -   introducing the fluid via the catheter.

24. The method of example 22 or example 23 wherein the fluid includes anepithelial-protective agent.

25. The method of any one of examples 22-24 wherein the fluid includespolyethylene glycol.

26. The method of any one of examples 22-25 wherein the fluid includes alocal anesthetic.

27. The method of any one of examples 22-26, further comprising coolingthe fluid to at least partially protect an inner portion of anepithelium of the renal pelvic wall.

28. The method of any one of examples 22-27 wherein the fluid includes avisualization medium.

29. The method of example 28, further comprising

-   -   imaging the renal pelvis; and    -   locating the focal zone based at least partially on the imaging.

30. A method for treating a human patient having a diagnosed conditionor disease associated with chronic sympathetic overactivity, the methodcomprising:

-   -   introducing a catheter through a ureter of the patient;    -   positioning a therapeutic element of the catheter within a renal        pelvis connected to the ureter; and    -   at least partially inhibiting sympathetic neural activity in        nerves proximate the renal pelvis using the therapeutic element.

31. The method of example 30 wherein the therapeutic element includesone or more electrodes configured to delivery radiofrequency energy.

32. The method of example 30 wherein re therapeutic element includes acryotherapeutic cooling assembly.

33. The method of example 30 wherein the therapeutic element isconfigured to deliver microwave energy.

34. The method of example 30 wherein the therapeutic element includes aplurality of electrodes having a bipolar configuration.

35. The method of any one of examples 30-34 wherein the therapeuticelement includes an opening, and at least partially inhibitingsympathetic neural activity includes introducing a chemical into a wallof the renal pelvis via the opening.

36. The method of example 35 wherein therapeutic element includes aneedle, and wherein the opening is at an end portion of the needle.

37. The method of example 35 or example 36 wherein the chemical is aneurotoxin.

38. The method of any one of examples 35-37 wherein the chemical isguanethidine.

39. The method of any one of examples 30-38, wherein at least partiallyinhibiting sympathetic neural activity includes

-   -   contacting a plurality of locations along the renal pelvic wall        with the therapeutic element, and    -   at least partially inhibiting sympathetic neural activity in        nerves proximate the locations, wherein the locations have        relatively-high concentrations of afferent renal nerve        terminals.

40. A method for treating a human patient having a diagnosed conditionor disease associated with systemic sympathetic overactivity orhyperactivity, the method comprising:

-   -   intravascularly positioning a neuromodulation assembly adjacent        to efferent and afferent renal nerves of the patient; and    -   selectively neuromodulating efferent renal nerves in the patient        compared to afferent renal nerves in the patient,    -   wherein selectively neuromodulating the efferent renal nerves        improves a measurable physiological parameter in the patient        corresponding to the diagnosed condition or disease associated        with systemic sympathetic overactivity or hyperactivity of the        patient

41. The method of example 40, further comprising reducing musclesympathetic nerve activity at least about 10% in the patient withinabout three months after selectively neuromodulating the afferent renalnerves.

42. The method of example 40 or example 41, further comprising reducingwhole body norepinephrine spillover in the patient.

43. The method of any one of examples 40-42, further comprising reducingwhole body norepinephrine spillover at least about 20% in the patientwithin about three months after selectively neuromodulating the afferentrenal nerves.

44. The method of any one of examples 40-43 wherein the patient has beendiagnosed as having cystinuria,

45. The method of any one of examples 40-44 wherein the patient has beendiagnosed as having an increased risk of developing kidney stonesrelative to the general population.

46. A method for treating a human patient, comprising:

-   -   intravascularly positing a therapeutic element at a position        within a renal artery or a renal branch artery of a kidney of        the patient; and    -   at least partially inhibiting sympathetic neural activity at a        portion of a renal plexus proximate the position using the        therapeutic element, wherein        -   the renal plexus has a first concentration of afferent renal            nerves at a first location proximate an ostium of the renal            artery,        -   the renal plexus has a second concentration of afferent            renal nerves at a second location closer to the kidney than            the first location,        -   the second concentration of afferent renal nerves is less            than about 50% of the first concentration of afferent renal            nerves, and        -   the position of the therapeutic element is proximate the            second location.

47. The method of example 46 wherein the second concentration ofafferent renal nerves is less than about 25% of the first concentrationof afferent renal nerves.

48. The method of example 46 or example 47 wherein

-   -   the position is a first position within a first renal branch        artery, and    -   the method further comprises        -   intravascularly positing the therapeutic element at a second            position within a second renal branch artery of the patient,            and        -   at least partially inhibiting sympathetic neural activity at            a portion of the renal plexus proximate the second position            using the therapeutic element.

XI. CONCLUSION

The above detailed descriptions of embodiments of the technology are notintended to be exhaustive or to limit the technology to the precise formdisclosed above. Although specific embodiments of, and examples for, thetechnology are described above for illustrative purposes, variousequivalent modifications are possible within the scope of thetechnology, as those skilled in the relevant art will recognize. Forexample, while steps are presented in a given order, alternativeembodiments may perform steps in a different order. The variousembodiments described herein may also be combined to provide furtherembodiments.

From the foregoing, it will be appreciated that specific embodiments ofthe technology have been described herein for purposes of illustration,but well-known structures and functions have not been shown or describedin detail to avoid unnecessarily obscuring the description of theembodiments of the technology. Where the context permits, singular orplural terms may also include the plural or singular term, respectively.

Moreover, unless the word “or” is expressly limited to mean only asingle item exclusive from the other items in reference to a list of twoor more items, then the use of “or” in such a list is to be interpretedas including (a) any single item in the list, (b) all of the items inthe list, or (c) any combination of the items in the list. Additionally,the term “comprising” is used throughout to mean including at least therecited feature(s) such that any greater number of the same featureand/or additional types of other features are not precluded. It willalso be appreciated that specific embodiments have been described hereinfor purposes of illustration, but that various modifications may be madewithout deviating from the technology. Further, while advantagesassociated with certain embodiments of the technology have beendescribed in the context of those embodiments, other embodiments mayalso exhibit such advantages, and not all embodiments need necessarilyexhibit such advantages to fall within the scope of the technology.Accordingly, the disclosure and associated technology can encompassother embodiments not expressly shown or described herein.

We claim:
 1. A method for treating a patient having a diagnosedcondition or disease associated with systemic sympathetic overactivity,the method comprising: cooling a medium within a renal pelvis of akidney of the patient, wherein the medium comprises anaturally-occurring fluid within the renal pelvis; and at leastpartially inhibiting autonomous neural activity in nerves that terminatewithin a chamber wall of the renal pelvis by at least heating thenerves, wherein the nerves are heated and the medium is cooled in amanner that causes therapeutically effective renal neuromodulation in azone within about 3 millimeters of an inner surface of the chamber wallof the renal pelvis while leaving epithelium of the renal pelvis viable.2. The method of claim 1 wherein heating the nerves selectively affectsafferent renal nerves that are located within the chamber wall of therenal pelvis compared to efferent renal nerves in the patient such thata greater percentage of afferent renal nerves are affected relative to apercentage of affected efferent renal nerves.
 3. The method of claim 1,further comprising: at least partially blocking a ureter to at leastpartially maintain the medium in the renal pelvis.
 4. The method ofclaim 1 wherein heating the nerves includes heating the nerves to atemperature sufficient to at least partially inhibit sympathetic neuralactivity in the nerves.
 5. The method of claim 4 wherein heating thenerves includes applying ultrasound energy to the nerves.
 6. The methodof claim 1 wherein heating the nerves includes focusing ultrasoundenergy in a focal zone within tissue proximate to the nerves.
 7. Themethod of claim 1, further comprising: introducing a catheter through aureter connected to the renal pelvis; and positioning a therapeuticelement of the catheter within the renal pelvis.
 8. The method of claim7, further comprising: heating the nerves using the therapeutic element.9. The method of claim 7 wherein the therapeutic element includes one ormore electrodes configured to deliver radiofrequency energy.
 10. Themethod of claim 7 wherein the therapeutic element includes a coolingassembly configured to cool the medium.
 11. The method of claim 7wherein the therapeutic element is configured to deliver microwaveenergy.
 12. The method of claim 7 wherein the therapeutic element isconfigured to deliver direct heat.
 13. The method of claim 1, whereinthe nerves are heated and the medium is cooled in a manner that createsa relatively-steep temperature gradient between the nerves and theepithelium.
 14. A method for treating a patient having a diagnosedcondition or disease associated with systemic sympathetic overactivity,the method comprising: introducing a catheter through a ureter connectedto a renal pelvis of a kidney of the patient; positioning a therapeuticelement of the catheter within the renal pelvis, wherein the therapeuticelement includes an opening; introducing an epithelial protective agentwithin the renal pelvis; introducing a drug into a fluid medium via theopening, wherein the fluid medium includes the epithelial protectiveagent; activating the drug or causing the drug to become morebioavailable; and at least partially inhibiting autonomous neuralactivity in nerves that terminate within a chamber wall of the renalpelvis via the fluid medium.
 15. The method of claim 14, wherein thetherapeutic element includes an electrode, and wherein activating thedrug or causing the drug to become more bioavailable further comprisesactivating the electrode to move at least a portion of the drug into awall of the renal pelvis by electrophoresis.
 16. The method of claim 14wherein the epithelial protective agent includes polyethylene glycol.17. The method of claim 14 wherein the drug includes a local anesthetic.18. The method of claim 14 further comprising: cooling the fluid mediumto at least partially protect an inner portion of an epithelium of awall of the renal pelvis.
 19. The method of claim 14 wherein the fluidmedium includes a visualization medium.